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Article

Synthesis and Application of a New Cyclic Phosphoric Acid in Enantioselective Three-Component Mannich Reactions

by
Giovanni Ghigo
*,
Alessio Robiolio Bose
and
Stefano Dughera
*
Department of Chemistry, University of Torino, Via Pietro Giuria 7, 10125 Torino, Italy
*
Authors to whom correspondence should be addressed.
Molecules 2025, 30(14), 2928; https://doi.org/10.3390/molecules30142928 (registering DOI)
Submission received: 11 June 2025 / Revised: 9 July 2025 / Accepted: 9 July 2025 / Published: 10 July 2025
(This article belongs to the Special Issue 30th Anniversary of Molecules—Recent Advances in Organic Chemistry)
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Abstract

A novel point-chiral six-membered cyclic phosphoric acid was synthesized starting from an enantiopure precursor via a concise three-step route. Its catalytic performance was evaluated in enantioselective three-component Mannich reactions. Under optimized conditions, the catalyst provided good yields and satisfactory enantiomeric excesses (up to 89%). The basic mechanism of the catalysis was also studied by the DFT method.

Graphical Abstract

1. Introduction

Organocatalysis, defined as the use of relatively small organic molecules to catalyze chemical reactions, is one of the fastest-growing areas in organic chemistry [1,2]. This technology, due to its many advantages, has established itself as the third pillar of asymmetric synthesis, alongside organometallic catalysis and biocatalysis [3,4,5,6].
The main advantages of organocatalysis can be summarized as follows: (i) environmental friendliness and low toxicity, (ii) high availability of organic reagents, (iii) low sensitivity to oxygen and moisture, and (iv) a large chiral pool.
According to List [7], organocatalysts can be classified into four main categories: Lewis acids, Lewis bases, Brønsted bases, and Brønsted acids. Among chiral Brønsted acids, chiral phosphoric acids (CPAs; Figure 1) have gained a prominent role and have been applied to a growing number of useful asymmetric protocols [8,9]. Most CPAs are based on axially chiral diols such as BINOL [10,11,12], SPINOL [13], VANOL [14] and VAPOL [15] and are characterized by a seven- or eight-membered cyclic phosphodiester core (in SPINOL derivatives, eight-membered).
On the other hand, there are only a few examples of point-chiral CPAs in the literature (Figure 2). Most of these are seven-membered rings derived from TADDOL [16]. Moreover, a small number of point-chiral six-membered cyclic phosphoric acids (e.g., phencyphos, chlocyphos, anicyphos) are known and used as resolving agents for chiral amines [17], but no applications in asymmetric synthesis have been reported.
Even rarer are examples of chiral five-membered cyclic phosphoric acids; essentially, only 2-hydroxy-4-methyl-1,3,2-dioxaphospholane 2-oxide is reported (Figure 2) [18].
In light of this, in our previous research (Figure 3), we synthesized three chiral five-membered cycloglycerophospates [19,20,21]. The last two, which show C2 symmetry, proved to be excellent chiral catalysts. Unfortunately, we were unable to convert them into the corresponding acids, as they decomposed in acidic environments.
Phencyphos and similar compounds were generally synthesized following Wynberg’s procedure [17], as shown in Scheme 1. The overall yields were quite good; in the best case (phencyphos), a yield of 76% was achieved. It should be noted that all the target compounds were obtained as racemic mixtures. To resolve these, various optically active bases were used (e.g., (−)-ephedrine, (+)-2-amino-1-phenyl-1,3-propanediol).
From this perspective, in the present work, we describe the synthesis of a new chiral six-membered cyclic phosphoric acid, starting from a chiral precursor, and its use as a chiral catalyst in multicomponent Mannich reactions.

2. Results and Discussion

The point-chiral six-membered CPA 7 was synthesized via a three-step protocol (Scheme 2). We chose to start from chiral compound 1, which is readily available and reasonably priced. In the first step, the ester group was reduced to an alcohol using NaBH4 in THF. Compound 2 was obtained in 97% yield.
In the second step, to eliminate a potentially reactive site (the chlorine atom), a nucleophilic substitution was carried out using sodium naphtholate (3). However, the results were unsatisfactory due to competition with the elimination reaction leading to ketone 5.
To address this issue, epoxide 6 was first synthesized by treating 2 with potassium carbonate [22]. Once 6 was obtained—although it was not isolated—it was reacted with 3, yielding the target adduct with an excellent yield. The introduction of a bulky group such as naphthol results in a structure with sufficient steric hindrance, which is useful for controlling enantioselectivity in subsequent reactions.
In the third and final step, adduct 4 was converted into chiral CPA 7 using POCl3 and triethylamine. Thereby, enantiomerically pure 7 was effectively obtained using a high-yield synthetic protocol (total yield calculated from 1 was 76%). The compound 7 was then tested as a chiral catalyst in a three-component Mannich reaction.
Mannich reactions are among the most important carbon–carbon bond-forming reactions in synthetic organic chemistry and are a standard method for synthesizing β-amino carbonyl compounds, which are key intermediates in the synthesis of many nitrogen-containing natural products and pharmaceuticals. These reactions can proceed via either a two- or a three-component protocol (Scheme 3; respectively, path red and path black) [23].
Stereoselective Mannich reactions catalyzed by chiral catalysts have received considerable attention, as they offer an efficient route for the enantioselective synthesis of β-amino carbonyl compounds [24,25]. Among these, chiral Brønsted acids have emerged as efficient catalysts, delivering high diastereo- and enantioselectivity. However, most chiral Brønsted acid-catalyzed Mannich reactions still involve imine catalysis in a two-component process [10,11,26].
Contrarily, the literature reports only a few examples of one-pot, three-component Mannich reactions catalyzed by chiral Brønsted acids [27,28,29,30,31].
With this in mind, we evaluated catalyst 7 in a three-component Mannich reaction. The model reaction involved benzaldehyde (8a), aniline (9a), and acetophenone (10a), using a catalytic amount of 7 under various conditions. As shown in Table 1, the best result was obtained under neat conditions at room temperature with 10 mol% of catalyst 1, which provided the target compound 11a in good yield and satisfactory enantioselectivity (ee 90%; Table 1, entry 6). Interestingly, in the presence of commercial phencyphos as catalyst, both the yields and the enantiomeric excesses of 11a were significantly lower (Table 1; entries 2–4).
To explore the scope and general applicability of this reaction, various substituted aromatic aldehydes 8, aromatic or aliphatic amines 9 and ketones 10 were used. The results are summarized in Table 2.
In particular, reactions between benzaldehyde (8a), acetophenone (10a), and a number of substituted aromatic amines 9a–g bearing either electron-withdrawing or electron-donating groups afforded satisfactory results in terms of both yield and enantioselectivity (Table 2; entries 1–7). Notably, the reaction outcomes were not significantly influenced by the electronic nature or the position of the substituents on the aromatic ring. Regarding aliphatic amines, the only appreciable results were obtained with benzylamine (9h; Table 2; entry 8).
Regarding the aromatic aldehydes 8, the presence of the nitro group in the meta position (aldehyde 8c) prevented the formation of the imine and consequently it was not possible to obtain adduct 11j (Table 2; entry 10). With the nitro group in the para position (aldehyde 8f), the intermediate imine was formed, even if slowly, and consequently it was possible to obtain adduct 11m (Table 2; entry 13). Good results were obtained in the presence of electron-donating groups (aldehydes 8b, 8d), with a halogen (aldehyde 8e; Table 2; entries 9,11,12) or with heteroaromatic aldehyde 8g (Table 2; entry 14). Electronic effects were also important for the ketones 10. The presence of electron-withdrawing groups, such as nitrogroup (ketone 10c), on the aromatic ring did not allow it to react with the imine intermediate (Table 2; entry 16). By contrast, good results were obtained in the precence of an electron donating group or a halogen (ketones 10b, 10d; Table 2; entries 15, 17). Moreover, by replacing 10a with aliphatic 10e, the main product of the reaction was 4-methylpent-3-en-2-one, which arose from the self-condensation of 10e (Table 2; entry 18).
It must be stressed that satisfactory results in terms of enantioselectivity were always obtained, regardless of the electronic effects of the substituents.
The mechanism of activation of the reaction among 8a, 9a and 10a by a non-chiral model of the catalyst X was studied by a computational DFT method (see the Supplementary Material SI § 1 for details on the method). The energy profiles and structures are illustrated in Figure 4. The pictures of the key transition structures, TSAdd-N, TSDe-H2O, TSAdd-C, and TSEnol, are shown in Figure 5. The reaction followed the typical Mannich mechanism [23].
The first step was the nucleophilic addition of 9a to 8a through TSAdd-N, where the catalyst allowed an indirect transfer of a proton from the amino group to the carbonyl, yielding the complex X-Ia between the adduct Ia and the catalyst. The second step, after reorientation of the catalyst in the complex X-IIa, consisted of dehydration through TSDe-H2O yielding the complex X-IIIa, which then lost a water molecule, yielding the complex X-IVa. Again, the catalyst acted through indirect proton transfer from the amino group to the hydroxyl. Finally, the addition through TSAdd-C of enol 12a to the imine IVa yielded a complex between X and the product 11a. Also, in this case the catalyst facilitated the proton transfer from the hydroxyl group of the enol to the imine/amine. The whole reaction was quite fast: the estimated rate constants at 273 K (0 °C) for the three steps (with [X] = 0.03 M) were kAdd-N = 9.0 • 107 M−1 s−1; kDe-H2O = 7.8 • 102 s−1; kAdd-C = 4.9 • 108 M−1 s−1.
Apparently, the rate-determining state is the dehydration, which determines the formation of the imine, as we will see when analyzing the reaction for other reactants (below). However, the real limiting phase, external to the mechanism described above, is the enolization of 10a to 12a through TSEnol (blue box in Figure 4). Despite the role of indirect proton transfer by the catalyst, this process is very slow (kEnol = 1.0 • 10−4 M−1 s−1) and thermodynamically disfavored (KEnol = 4.3 • 10−11). Therefore, even if the imine is quickly formed, one will find a very small concentration of the enol 12a. This explains why the reaction requires a long time (24 h or more).
In order to explain why in some selected cases (Table 2, entries 10, 13, 16) less or no product was obtained, we extended the computational study to some critical points of the reaction.
The formation of the imines IV is the first phase of the reaction and the rate-determining step is the dehydration (TSDe-H2O). If we compare the free energies for this step (Table 3, bold numbers), for the reaction of 9a with 8a (Table 2, entry 1), with 8f (Table 2, entry 13) or 8c (Table 2, entry 10), we can observe that, for the latter, the free energy of TSDe-H2O was 2.5 kcal mol−1 higher than that for 8a.
This means that the formation of the imine is 95 times slower. This can explain why no product or imine was recovered (Table 2; entry 10 and note 4,). With 8f, the free energy of TSDe-H2O was 1.3 kcal mol−1 higher than that for 8a. This means that the imine is formed more slowly (9 times slower), yielding 11m in smaller yields (Table 2; entry 13).
In the reaction with 10c (Table 2, entry 16), despite a slightly less unfavorable free energy (12c is 12.1 kcal mol−1 above 10c compared to 13.0 kcal mol−1 for 12a above 10a), the free energy barrier for enolization was 1.3 kcal mol−1 higher (22.1 kcal mol−1). This led to a rate for the formation of the enol 12c 12 times slower than that for 12a. Therefore, once formed from 8a and 9a, the imine (Table 2; entry 16, note 5) could not find enough enol to complete the reaction.
In entry 18, the ketone is acetone (10e). In this case, only the product of the aldol condensation was identified (Table 2; entry 18, note 6). The comparison of the activation free energies (Table 4) for the additions of the enols 12a or 12e to the imine IVa (TSAdd) or to the ketones 10a and 10e (TSAldC) shows that the former was preferred when the ketone was benzophenone 10a (its enol 12a), while when the ketone was acetone (10e and 12e) the addition leading to enol condensation was preferred. This could be due to the higher reactivity of acetone, whose carbonylic carbon atom presents a partial charge of 0.61 e− and a localized π*CO, while in benzophenone the partial charge on the carbonylic carbon is slightly smaller (0.59) and the π*CO is partially delocalized on the aromatic ring.
Based on the mechanism described in Figure 4, it can be reasonably assumed that in TSAdd-C, the nucleophilic attack of enol 12a occurred predominantly from only one direction, leading to the formation of 11a with good enantiomeric excesses. Therefore, further studies were carried out with a chiral model of catalyst 7. However, in the optimization of TSAdd-C leading to products R and S, we identified several conformations, all close in energy and free energy, that did not give clear indications (see Supplementary Material, Table on page S-8). While there was a difference of 1.3 kcal mol−1 in terms of energy in favour of the lowest transition structure yielding the R product, TS(R)(a), with respect to that yielding the S product, TS(S)(a), the free energy values reduced the difference to less than 0.1 kcal mol−1, and more so between different TS, TS(R)(e) and TS(R)(d).
This is possibly due to the fact that to reproduce the enantiomeric excesses requires an accuracy in the calculation of the transition structures (less than 1 kcal mol−1) that goes beyond that of available computational methods (ca. 2 kcal mol−1) [32].

3. Materials and Methods

3.1. General

All reagents and solvents were purchased from commercial sources (Merck, Milano, Italy; Thermo Fisher Scientific, Monza, Italy; Carlo Erba Reagents, Cornaredo (MI), Italy) at the highest available purity grade and used without further purification. All reactions were carried out in open air glassware and monitored by GC-FID and GC-MS. TLC were performed on Merck silica gel 60 (70-230 mesh ASTM) and GF 254. Mass spectra were recorded on an HP 5989B mass selective detector (Hewlett-Packard, Cernusco sul Naviglio (MI), Italy) connected to an HP 5890 GC (Hewlett-Packard, Cernusco sul Naviglio (MI), Italy) with a methyl silicone capillary column. GC FID analyses were performed on a Perkin Elmer AutoSystem XL GC (Perkin-Elmer, Milano, Italy) with a methylsilicone capillary column. 1H NMR and 13C NMR spectra were recorded on a Brucker spectrometer at 400 and 100 MHz (Brucker, Milano, Italy). Chiral analyses were performed on an Essential LC-16 series HPLC (Shimadzu, Milano, Italy) using a Daicel CHIRALPAK-IG (250 x 4.6 mm, 5 mm; Daicel Corporation, Japan, Tokyo) eluting with i-PrOH and n-hexane. For determination of the optical rotation, a Jasco P-2000 polarimeter (Jasco, Cremella (LC), Italy) was used. IR spectra were recorded on an IR Perkin-Elmer UATR-two spectrometer (Perkin Elmer, Milano, Italy). The structures and purity of all products obtained in this research were confirmed by spectroscopic data (NMR, GC-MS, IR) datathat are reported in the Supplementary Material. Satisfactory microanalyses were obtained for all new compounds.

3.2. (+)-2-Hydroxy-4-((naphthalen-2-yloxy)methyl)-1,3,2-dioxaphosphinane 2-oxide (7)

3.2.1. Synthesis of (S) (−)-4-Chlorobutane-1,3-diol (2)

As reported in the literature [33], THF (15 mL) and, under stirring, NaBH4 (1.14 g, 30 mmol) were added in a 50 mL flask. The resulting suspension was stirred at 40 °C for 1 h. Then, to this suspension, (S) ethyl 4-chloro-3-hydroxybutirrate (1; 3.34 g, 20 mmol), dissolved in THF (10 mL) was added dropwise. The mixture was stirred at 40 °C for 5 h, until the TLC (eluent PE/ethyl acetate 3:2), GC and GC-MS analyses showed the complete disappearance of 1. After acidifying (pH 5) with HCl 2M (1 mL), a white solid precipitated, which was removed by filtration with a Bückner funnel. The residual THF resulting from filtration was evaporated under reduced pressure. The resulting colorless oil was the virtually pure title compound (2; 2.39 g, 96% yield).
[α]D21 = −22.9 (c = 1.00 in MeOH; Lit. [33] 22.3 for R enantiomer); 1H NMR (400 MHz, CDCl3): δ = 4.12–4.06 (m, 1H), 3.94–3.84 (m, 2H), 3.64 (dd, J1 = 11.2 Hz, J2 = 4.0 Hz, 1H), 3.55 (dd, J1 = 11.2 Hz, J2 = 4.0 Hz, 1H), 2.37 (br s, 2H), 1.85–1.80 (m, 2H); 13C NMR (100 MHz, CDCl3): δ = 68.7, 58.3, 47.7, 33.7; IR (neat) ν = 3345 (OH), 3321 (OH) cm−1. MS: m/z 124 (M+·).

3.2.2. Synthesis of (−)-4-(Naphthalen-2-yloxy)butane-1,3-diol (4)

As reported in the literature [22], anhydrous K2CO3 (2.76 g, 20 mmol) and MeOH (10 mL) were added in a 50 mL flask. To the resulting turbid solution, 2 (1.24 g, 10 mmol) dissolved in MeOH (5 mL) was added at rt under stirring. After 2 h, TLC (eluent PE/ethyl acetate 3:2) and GC-MS analyses showed the disappearance of 2 and the presence of epoxide 6 (MS: m/z 88 (M+)), which was not isolated, but was reacted in situ. Then, sodium naphthalen-2-olate (1.99, 12 mmol) was added in a single portion. The mixture was stirred at rt for a further 3 h, until the TLC (eluent PE/ethyl acetate 3:2), GC and GC-MS analyses showed the complete disappearance of 6. MeOH was evaporated under reduced pressure and the crude residue was purified in a short chromatography column (eluent PE/ethyl acetate 1:4). The resulting white solid was the pure title compound (4; 2.20 g, 95% yield).
[α]D21 = −12.9 (c = 1.00 in MeOH); 1H NMR (400 MHz, CD3OD): δ =7.78–7.75 (m, 3H), 7.44 (t, J = 7.6 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 4.22–4.17 (m, 1H), 4.13–4.03 (m, 2H), 3.82–3.79 (m, 2H), 1.97–1.89 (m, 1H), 1.87–1.79 (m, 1H); 13C NMR (100 MHz, CD3OD): δ = 156.9, 134.7, 129.1, 128.9, 127.2, 126.5, 125.9, 123.3, 118.5, 106.4, 72.0, 67.1, 58.5, 35.9. IR (neat) ν = 3461 (OH), 3408 (OH) cm−1. Elemental analysis calcd (%) for C14H16O3: C 72.39; H 6.94; found: C 71.99; H 7.02.

3.2.3. Synthesis of (+)-2-Hydroxy-4-((naphthalen-2-yloxy)methyl)-1,3,2-dioxaphosphinane-2-oxide (7)

As reported in the literature [20], THF (5 mL) and POCl3 (0.77 g, 5 mmol) were added in a 50 mL flask. The mixture was cooled to −20 °C and NEt3 was added (0.51 g, 5 mmol). At this point, a solution of 4 (0.23 g, 1 mmol) in THF (5 mL) was added dropwise. The reaction mixture was stirred at −20 °C for 1 h and at rt for additional 2 h. Then, it was carefully quenched in a saturated solution of NaHCO3 (about 20 mL) and was extracted with ethyl acetate (15 mL). At the end of extraction, the organic phase was eliminated and H2O was evaporated under reduced pressure. In order to separate the target product from undesired byproducts, a trituration with methanol (50 mL) was performed. The resulting white waxy solid was dissolved in H2O (2 mL). The solution was acidified with HCl 2M (2 mL). A white solid precipitate was isolated by filtration with a Büchner funnel and was the pure title compound (7; 0.24 g, 82% yield).
[α]D21 = + 9.4 (c = 1.00 in MeOH); 1H NMR (400 MHz, CD3OD): 7.66–7.44 (m, 3H), 7.32 (t, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 7.30 (m, 1H), 7.24–7.20 (m, 1H), 7.15–7.14 (m,1H), 7.07–7.04 (m, 1H), 4.82–4.78 (m, 1H), 4.41–4.27 (m, 2H), 4.13–4.12 (m, 2H), 2.18–2.08 (m, 1H), 1.89–1.86 (m, 1H); 13C NMR (100 MHz, CD3OD): 156.4, 134.6, 129.3, 129.1, 127.2, 126.5, 126.0, 123.5, 118.2, 106.6, 77.7 (d, J = 5.7 Hz), 69.7 (d, J = 9.8 Hz), 67.0 (d, J = 6.1 Hz), 27.8 (d, J = 5.6 Hz). 31P NMR (162 MHz, CD3OD): −5.1. IR (neat) ν = 3042 (OH)cm−1; elemental analysis calcd (%) for C14H15O5P: C 57.15; H 5.14; found: C 56.99; H 5.21.

3.3. (+)-7 as a Catalyst in Mannich Reaction: General Procedure

(+)-7 (10 mol%, 30 mg, 0.1 mmol) was added to stirring mixtures of aldehydes 8 (1 mmol), amines 9 (1 mmol) and ketones 10 (1 mmol). The mixtures were stirred at r.t. for the times listed in Table 2 until the GC and GC-MS analyses showed the complete disappearance of the starting compounds and the complete formation of β-aminoketones 11. Cold H2O (2 mL) was added to the reaction mixture, under vigorous stirring. The resulting solids were filtered with a Hirsch funnel and washed with additional cold H2O (1 mL) and petroleum ether (1 mL). Virtually pure (TLC, GC, GC-MS, 1H NMR, 13C NMR) β-aminoketones 11 were obtained.

4. Conclusions

We synthesized a new point-chiral six-membered cyclic phosphoric acid in three steps from a commercially available chiral precursor (total yield 76%). This catalyst demonstrated good performance in asymmetric three-component Mannich reactions, delivering products with good yields (15 positive examples; average yield 80%) and satisfacyory enantioselectivity (15 positive examples; average ee 92.1%). Its operational simplicity, good functional group tolerance, and potential for structural modification make it a valuable addition to the toolbox of chiral Brønsted acid catalysts. Finally, it must be stressed that this new catalyst has a performance comparable to those of axially chirally BINOL-derived phosphoric acids widely used as asymmetric catalysts in the Mannich reaction [10,11,27].

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules30142928/s1. Computational method: S-2; tables with absolute and relative energies: S-4; pictures and Cartesian coordinates of structures: S-11; NMR spectra of precursors 2, 4 and catalyst 7: S-49; physical and spectroscopic data of compounds 11: S-55; NMR spectra of compounds 11: S-59; chiral analyses of compounds 11: S-74. Includes refs. [34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50].

Author Contributions

Conceptualization, S.D. and G.G.; methodology, S.D.; software, G.G.; validation, S.D. and G.G.; formal analysis, S.D.; investigation, S.D., G.G., A.R.B.; resources, S.D.; data curation, S.D.; writing—original draft preparation, S.D. and G.G.; writing—review and editing, S.D. and G.G.; visualization, S.D.; supervision, S.D.; project administration, S.D.; funding acquisition, S.D. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data reported in this article can be obtained from the authors upon reasonable request. Samples of the catalyst (+)-7 and adducts 11 are available from the authors.

Acknowledgments

This work was supported by the University of Torino and by Ministero dell’Università e della Ricerca Scientifica (MIUR). The authors acknowledge support from the Project CH4.0 of the Chemistry Department of UNITO under MIUR program “Dipartimenti di Eccellenza 2—3–2027” (CUP: D13 C22003520001).

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 30 02928 g001
Figure 1. Various axially chiral CPAs.
Figure 1. Various axially chiral CPAs.
Molecules 30 02928 g001
Molecules 30 02928 g002
Figure 2. Various point-chiral cyclic CPAs.
Figure 2. Various point-chiral cyclic CPAs.
Molecules 30 02928 g002
Molecules 30 02928 g003
Figure 3. Five-membered cycloglycerophospates.
Figure 3. Five-membered cycloglycerophospates.
Molecules 30 02928 g003
Molecules 30 02928 sch001
Scheme 1. Synthesis of phencyphos.
Scheme 1. Synthesis of phencyphos.
Molecules 30 02928 sch001
Molecules 30 02928 sch002
Scheme 2. Synthesis of CPA 7.
Scheme 2. Synthesis of CPA 7.
Molecules 30 02928 sch002
Molecules 30 02928 sch003
Scheme 3. Two- or three-component Mannich reactions.
Scheme 3. Two- or three-component Mannich reactions.
Molecules 30 02928 sch003
Molecules 30 02928 g004
Figure 4. Energy profiles (in kcal mol−1) for the Mannich reaction among 8a, 9a and 10a catalyzed by an achiral model X of the catalyst 7. Dashed line, E+ZPE; thick line, free energy at 273.15 K (0 °C). Red values are free energy barriers with respect to the originating starting minima. The blue box reports the catalyzed enolization of 10a to 12a with the relative free energies.
Figure 4. Energy profiles (in kcal mol−1) for the Mannich reaction among 8a, 9a and 10a catalyzed by an achiral model X of the catalyst 7. Dashed line, E+ZPE; thick line, free energy at 273.15 K (0 °C). Red values are free energy barriers with respect to the originating starting minima. The blue box reports the catalyzed enolization of 10a to 12a with the relative free energies.
Molecules 30 02928 g004
Molecules 30 02928 g005
Figure 5. Transition structures for the Mannich reaction among 8a, 9a and 10a catalyzed by an achiral model X of catalyst 7.
Figure 5. Transition structures for the Mannich reaction among 8a, 9a and 10a catalyzed by an achiral model X of catalyst 7.
Molecules 30 02928 g005
Table 1. Trial reactions.
Table 1. Trial reactions.
Molecules 30 02928 i001
Entry CatalystAmount (%)Solvent T (°C)Time (h) Yield (%) of 11a 1,2 Ee (%) 3
1--neat204- 4-
2Molecules 30 02928 i0025toluene20242738.2
3Molecules 30 02928 i0035neat20243349.1
4Molecules 30 02928 i00410neat20244049.3
575neat20244089.4
6710neat 20248590.1
7710neat048- 5-
8710DCM2048- 5-
9710toluene2024 h4072.5
1 Reactants 8a, 9a, 10a were in equimolecular amount (1 mmol); 2 Yield refers to pure and isolated 11a obtained after filtering via Büchner funnel and washing the crude residues with a small amount of H2O and petroleum ether; 3 The enantiomeric excesses (ee) were determined by chiral analyses on HPLC connected to a chiral column. 11a is a (+) enantiomer; 4 GC-MS analysis of the crude residue showed the presence of N,1-diphenylmethanimine, MS: m/z 181 (M)+ and unreacted 10a. N,1-diphenylmethanimine was isolated in approximate quantitative yield. Even extending the reaction time to 24 h, only N,1-diphenylmethanimine was obtained; 5 The reaction was not complete.
Table 2. Three-component Mannich reaction between 8, 9, and 10 catalyzed by 7.
Table 2. Three-component Mannich reaction between 8, 9, and 10 catalyzed by 7.
Molecules 30 02928 i005
EntryAr in 8Z in 9W in 10Time (h)Products 11Yield 1,2 (%)Ee 3 (%)
1C6H5
8a		C6H5
9a		C6H5
10a		2411a8590.3
2C6H5
8a		2-NO2C6H4
9b		C6H5
10a		2411b8791.5
3C6H5
8a		3-FC6H4
9c		C6H5
10a		2411c9191.7
4C6H5
8a		4-MeC6H4
9d		C6H5
10a		3611d8292.9
5C6H5
8a		4-NO2C6H4
9e		C6H5
10a		2411e9195.0
6C6H5
8a		4-BrC6H4
9f		C6H5
10a		2411f9293.1
7C6H5
8a		2,6-(CH3)2C6H3
9g		C6H5
10a		2411g8289.7
8C6H5
8a		C6H5CH2
9h		C6H5
10a		3611h8792.6
93-MeOC6H4
8b		C6H5
9a		C6H5
10a		3611i9292.9
103-NO2C6H4
8c		C6H5
9a		C6H5
10a		2411j- 4-
114-MeC6H4
8d		C6H5
9a		C6H5
10a		4811k8191.7
124-ClC6H4
8e		C6H5
9a		C6H5
10a		4811l8792.6
134-NO2C6H4
8f		C6H5
9a		C6H5
10a		4811m6795.1
142-thienyl
8g		C6H5
9a		C6H5
10a		2411n9089.6
15C6H5
8a		C6H5
9a		3-MeOC6H4
10b		2411o9390.1
16C6H5
8a		C6H5
9a		4-NO2C6H4
10c		2411p- 5-
17C6H5
8a		C6H5
9a		4-ClC6H4
10d		4811q9292.8
18C6H5
8a		C6H5
9a		Me
10e		2411r- 6-
1 Reactants 8, 9, 10 were in equimolecular amounts (1 mmol) in the presence of 10 mol% of catalyst 7; 2 Yields refers to pure and isolated 11 obtained after filtering via Büchner funnel and washing the crude residues with a small amount of H2O and petroleum ether; 3 The enantiomeric excesses (ee) were determined by chiral analyses on HPLC connected to a chiral column. All compounds 11 are (+) enantiomers; 4 Only the starting products 8c, 9a, 10a were recovered; 5 Only N,1-diphenylmethanimine was formed; MS: m/z 181 (M)+. 6 The main product was 4-methylpent-3-en-2-one; MS: m/z 98 (M)+.
Table 3. The free energies (in kcal mol−1, 273 K) for the formation of the complex X-IV between the catalyst X and the imines IV from 9a and 8a, 8f or 8c.
Table 3. The free energies (in kcal mol−1, 273 K) for the formation of the complex X-IV between the catalyst X and the imines IV from 9a and 8a, 8f or 8c.
Benzaldehyde (8a)4-Nitrobenzaldehyde (8f)3-Nitrobenzaldehyde (8c)
TSAdd-N5.84.96.4
X-I−2.1−3.1−1.0
TSDe-H2O10.211.412.7
X-IV−4.7−8.7−3.1
Table 4. The free energy barriers (in kcal mol−1, 273 K) for the addition of the enols 12a (from benzophenone 10a) and 12e (from acetone 10e) to the imine IVa and to the ketones 10a and 10e.
Table 4. The free energy barriers (in kcal mol−1, 273 K) for the addition of the enols 12a (from benzophenone 10a) and 12e (from acetone 10e) to the imine IVa and to the ketones 10a and 10e.
Acetophenone (10a)Acetone (10e)
TSAdd6.87.5
TSAldC9.26.9
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Ghigo, G.; Robiolio Bose, A.; Dughera, S. Synthesis and Application of a New Cyclic Phosphoric Acid in Enantioselective Three-Component Mannich Reactions. Molecules 2025, 30, 2928. https://doi.org/10.3390/molecules30142928

AMA Style

Ghigo G, Robiolio Bose A, Dughera S. Synthesis and Application of a New Cyclic Phosphoric Acid in Enantioselective Three-Component Mannich Reactions. Molecules. 2025; 30(14):2928. https://doi.org/10.3390/molecules30142928

Chicago/Turabian Style

Ghigo, Giovanni, Alessio Robiolio Bose, and Stefano Dughera. 2025. "Synthesis and Application of a New Cyclic Phosphoric Acid in Enantioselective Three-Component Mannich Reactions" Molecules 30, no. 14: 2928. https://doi.org/10.3390/molecules30142928

APA Style

Ghigo, G., Robiolio Bose, A., & Dughera, S. (2025). Synthesis and Application of a New Cyclic Phosphoric Acid in Enantioselective Three-Component Mannich Reactions. Molecules, 30(14), 2928. https://doi.org/10.3390/molecules30142928

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