Chiral thiourea derivatives as organocatalyts in the enantioselective Morita-Baylis-Hillman reactions

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Morita 14 described a novel reaction between various aldehydes and acrylic compounds catalysed by a tertiary phosphine (tricyclohexylphosphine) and yielding vinylic compounds.Subsequently, in 1972, Baylis and Hillman 15 reported a similar reaction between acetaldehyde and ethyl acrylate or acrylonitrile.Instead of phosphines, they used 1,4-diazabicyclo[2.2.2]octane (DABCO) as a Lewis base to obtain products similar to those of Morita's study (Scheme 1).Since then, various chiral catalysts such as chiral Lewis acid or Brønsted-Lowry acid catalysts, [16][17][18] chiral amino-or phosphino-type catalysts, [19][20][21] chiral amino acid derivatives, 22,23 a chiral thiourea-type catalyst 24 and chiral ionic liquids 25 have been reported for this asymmetric catalytic process.These chiral catalysts have been developed for intermolecular MBH reactions. 26Optically active -hydroxy--methylene carbonyl compounds are useful intermediates in natural product synthesis.
To synthesise these compounds, several enantioselective versions of the MBH reaction involving a chiral catalyst have been reported. 27Barrett et al. 28 used chiral bicyclic pyrrolizidine derivatives (A) as asymmetric catalysts for the MBH reaction of ethyl vinyl ketone and an aromatic aldehyde.Hatakeyama et al. 29 used β-isocupreidine (B) to catalyse the asymmetric MBH reaction between aldehydes and the strongly activated Michael acceptor 1,1,1,3,3,3-hexa-fluoroisopropyl acrylate (HFIP).Hayashi et al. 30 developed chiral diamines (C) as catalysts for the MBH reaction of MVK and electron-deficient benzaldehyde, affording adducts with enantioselectivities up to 75 % (Scheme 2).
2][33] In the presence of L-valine-derived phosphinothiourea (D), the MBH products were obtained in good enantioselectivities (up to 83 % ee) (Scheme 2). 34The intramolecular MBH reaction can be performed when suitably oriented electrophilic and activated alkene moieties are present in the same molecule, but few examples of intramolecular MBH reactions are found in the literature.

reported an intramolecular MBH reaction
In this study, the intermolecular MBH reaction of an aromatic aldehyde with methyl vinyl ketone (MVK) and the intramolecular MBH reaction of ω-formyl-enone catalysed by the thioureas 7a-d and 11a-d are presented.

Results and Discussion
The synthesis of chiral thiourea derivatives 7a-d.The synthesis of -amino alcohol 6 from (1S)-(-)-camphor was performed according to the literature procedure. 42,43Chiral amino alcohol-based thioureas 7a-d were easily obtained by condensation of -amino alcohol 6 with 1.1 equiv. of the corresponding isothiocyanate in CH 2 Cl 2 at room temperature (Scheme 4).
For the synthesis of 7a-d and 11a-d, chiral compounds 6 and 10 were stirred with 1.1 equiv. of the corresponding isothiocyanates at room temperature (Scheme 4).

The enantioselective MBH reaction of p-nitrobenzaldehyde with methyl vinyl ketone (MVK)
To determine the best catalyst, the model reaction of p-nitrobenzaldehyde and MVK was initially performed in the presence of 10 mol% of catalysts 7 and 11a-d, and the results are summarised in    The enantioselectivity decreased with an increase in the reaction time from 30 to 60 min.In the presence of 7a, a higher conversion (85 % yield) was obtained after 60 min, but the enantioselectivity decreased (72 % ee) (entry 11).The MBH product after 45 min was obtained in 78 % chemical yield with 92 % ee.The absolute configuration of the intermolecular MBH products, R, was assigned by comparing the retention time (chiral HPLC) with its literature values. 23,30,31,33,48ecause 7a gave the highest enantioselectivity in the MBH reaction of p-nitrobenzaldehyde with MVK, it was identified as most effective among the chiral ligand series (Table 1, entry 10) and was selected for optimising further the reaction conditions.
Then, the solvent effect on the MBH reaction of p-nitrobenzaldehyde with MVK was investigated using 7a as the chiral ligand.The results, outlined in Table 2, show that the highest enantiomeric excess (92 %) was observed in CH 2 Cl 2 .In polar solvents such as EtOH, DMF and MeCN, the MBH adduct 3a was obtained in low yield and ee (Table 2, entries 5-7).The lowest enantioselectivity was obtained in DMSO.Increasing the reaction temperature from room temperature to 40 C decreased the ee value to 77 % (Table 2, entries 4, 9), whereas decreasing the reaction temperature to −15 C obtained the corresponding product in 45 % yield with 65 % ee(Table 2, entry 10).a The reaction were performed using 10 mol% of chiral ligand, 5 equiv of MVK in 1 mL solvent at room temperature.b Isolated yields.c Determined by HPLC using Chiral OD-H column.
To investigate the effect of electron-withdrawing and electron-donating substituents, the asymmetric MBH reaction was performed with different aromatic aldehydes using conditions optimised for ligand 7a (10 mol% of 7a catalyst, 5 equiv. of MVK, CH 2 Cl 2 as a solvent, room temperature).The results are summarised in Table 3.The electronic effects on the aromatic ring of the aldehyde affected the reactivity and selectivity.Electron-withdrawing substituents gave higher enantioselectivities than did electron-donating substituents.It is known that the electrophilicity of the carbonyl carbon atom in aryl aldehydes is increased by electronwithdrawing groups and decreased by electron-donating groups; therefore, the substrates with an electronwithdrawing substituent are expected to afford a faster reaction, leading to higher enantioselectivity.In fact, a lower enantioselectivity was observed for the meta-substituted benzaldehyde compared to that of its relevant para-substituted analogue (entry 3 and 4).With ligand 7a, the lowest enantiomeric excesses were observed for aromatic aldehydes bearing ortho substituents, probably due to the ortho effects (entry 2 and 7).In the presence of ligand 7a, the non-substituted benzaldehyde afforded the product with 85 % ee but in low yield (62 %).The yields and ee values decreased (62 % yield, 55 % ee) when the methoxy group on the phenyl ring was at the para position(entries 10).Chiral thiourea derivatives 7 and 11a-d were examined in the enantioselective intramolecular MBH reaction of ω-formyl-enone as the model substrate (Scheme 6).-Amino alcohol-based thioureas 7a were used as catalysts in the intramolecular reaction of substrate 12a in CH 2 Cl 2 at room temperature, and the MBH product 13a was obtained in 65 % chemical yield with good enantioselectivity (72 % ee).As shown in Table 4, the structure of the chiral ligands significantly affected the enantioselectivity and the chemical yield.The thiourea moiety of the chiral ligands played an important role in obtaining a high yield and enantioselectivity.Chiral thiourea derivatives 7b and 11b, bearing strong electron-withdrawing substituents at the phenyl ring, afforded the corresponding product in 63 % chemical yield with 95 % ee and in 65 % chemical yield with 94 % ee, respectively.Chiral ligand 7b provided the corresponding product in higher enantioselectivity and chemical yield than ligands 7a,c,d did (Table 4, entries 1-4).These observations were agreement with the observations of Wu et al. 39 The absolute configuration of the intramolecular MBH products is R-configuration, which was assigned by comparing the retention time (chiral HPLC) with those reported in the literatures. 30,39,41,48,46ecause 7b gave the highest enantioselectivity in the intramolecular MBH reaction, it was identified as most effective among the chiral ligand series (Table 4, entry 2) and was selected for optimising further the reaction conditions.
To further improve the enantioselectivity of 12a, the effect of solvent on the enantioselective intramolecular MBH reaction of ω-formyl-enone was investigated (Table 5, entries 1-8).The enantioselective intramolecular MBH reaction was performed in solvents such as n-hexane, toluene, CHCl 3 , CH 2 Cl 2 , THF, acetone, CH 3 CN, DMF, MeOH and EtOH.Table 5 shows that CH 2 Cl 2 was the most appropriate solvent (entry 4).In DMF, the corresponding product was obtained in 10 % chemical yield with 25 % ee (entry8).In MeOH, the MBH product 13a was obtained in moderate chemical yield (72 %) but with poor enantioselectivity (12 % ee) (entry 9). a The reaction were performed using 10 mol% of chiral ligand, 5 equiv of ω-formyl-enone in 1 mL solvent at room temperature.b Isolated yields.c Determined by HPLC using Chiral OD-H column.
The enantioselective intramolecular MBH reaction involving various ω-formyl-enone substrates was investigated, and the results are summarised in Table 6.All the substituted aromatic enones were converted to the MBH reaction product in 62-95 % ee.As shown in Table 6, the substrates with an electron-withdrawing substituent at the para position of the phenyl ring afforded higher enantioselectivity than those with an electron-donating substituent or without a phenyl substituent.
With a substrate-bearing substituent at the ortho position of the phenyl group, the corresponding product was obtained in excellent yield with poor enantioselectivity, due to the ortho effect (entries 2 and 8).

Conclusions
In summary, we have developed the MBH reaction of an aromatic aldehyde with MVK and the intramolecular MBH reaction of ω-formyl-enone catalysed by thioureas 7a-d and 11a-d.The reaction proceeds under very mild conditions to quickly afford the desired product in good to excellent yields with generally excellent enantiomeric excesses.The use of (1R,2S)-7b as a chiral ligand bearing a strong electron-withdrawing substituent at the phenyl group afforded the hydroxyl enone with low enantioselectivity (40 % ee) in the intermolecular MBH reaction, whereas the same ligand gave the highest enantioselectivity (97 % ee) in the intramolecular MBH reaction.Thiophene ring-containing thiourea derivatives bearing a strong electronwithdrawing substituent on the phenyl group 11b gave a high enantioselectivity in the intermolecular MBH reaction (85 % ee), whereas the same ligand afforded the cyclic hydroxyl enones with excellent enantioselectivity (94 % ee).The application of these ligands to the other asymmetric reactions is now under investigation.

Experimental Section
General.Reagents and solvents were purchased from Aldrich, Merck and Fluka.All solvents were dried before use according to the standard procedures.All reactions were carried out under Ar atmosphere and monitored Synthesis of chiral diamine 10.According to our previously procedure, 46,47 the formylation of 2-methyl thiophene was performed according to Vismeier Haack method.5-Methyl thiophene-2-carbaldehyde 8 (5mmol) were dissolved in 10 mL benzene to which was added (1S,2S)-1,2-diphenylethane-1,2-diamine (5 mmol) under nitrogen atmosphere.The mixture was refluxed for 4 h and water was removed in a Dean-Stark trap.Reaction was controlled by TLC.Imine was concentrated to dryness without purification.The synthesized imine was dissolved in 15 mL Et 2 O and added to a suspension of 1.40 mmol LiAlH 4 in 10 mL Et 2 O.The mixture was refluxed for 8 h and controlled by TLC.When the reaction was completed, the mixture was cooled to room temperature and quenched with 15 mL water.It was extracted with ether (3x10 mL) and dried over MgSO 4 .The mixture was filtered and the solvent was evaporated.Crude product 10 were purified by flash column chromatography(EtOAc-hexane, 1:1)

Table 1 .
Screening of the chiral ligands for the MBH reaction of p-nitrobenzaldehyde with methyl vinyl ketone (MVK) a b Isolated yields.c Determined by HPLC using Chiral OD-H column

Table 2 .
Effects of the solvents and reaction temperature on the MBH reaction of p-nitrobenzaldehyde with MVK a

Table 3 .
The enantioselective MBH reaction involving various substituted aldehydes a a The reaction were performed using 10 mol% of chiral ligand, 5 equiv of MVK in 1 mL solvent at room temperature.b Isolated yields.c Determined by HPLC using Chiral OD-H column The enantioselective intramolecular MBH reaction of ω-formyl-enone catalyzed by -amino alcohol-based thiourea 7 and 11a-d C O OH 12a 13a Scheme 6. Enantioselective intramolecular MBH reaction.Arkivoc 2020, vi, 21-38 Aydin, A. E. Page 28 © AUTHOR(S)

Table 4 .
Catalysts screening for the intramolecular MBH reaction of 12a a a The reaction were performed using 10 mol% of chiral ligand, 5 equiv of ω-formyl-enone in 1 mL solvent at room temperature, 45 min.b Isolated yields.c Determined by HPLC using Chiral OD-H column.

Table 5 .
The effect of the solvents on the intramolecular MBH reaction a

Table 6 .
The enantioselective intramolecular MBH reaction involving various ω-formyl-enone substrates a a The reaction were performed using 10 mol% of chiral ligand, 5 equiv of ω-formyl-enone in 1 mL CH 2 Cl 2 at room temperature.b Isolated yields.c Determined by HPLC using Chiral OD-H column.
by thin-layer chromatography (TLC) on Merck silica gel plates (60 F-254) using UV light or phosphomolybdic acid in methanol.E. Merck silica gel (60, particle size 0.040-0.063mm) was used for flash chromatography.All NMR spectra were recorded on a Bruker DPX-400 MHz spectrometer at room temperature.Chemical shifts (parts per million) are reported relative to TMS.Coupling constant are expressed as J values in Hertz.Thin layer chromatography (TLC) was performed using Merck Kieselgel 60 F254.Elemental analyses (C, H, N, S) were carried out on a Carlo Erba Model Thermo Scıentıfıc Flash 2000 elemental analyzer.Optical rotations were recorded on a Autopol IV polarimeter.All melting points were measured with an Electrothermal melting point instrument.Elemental analyses were carried out on a LECO CHNS-932 series analyzer.Enantiomeric excesses were determined by HPLC analysis using a Shimadzu and Thermo Finnigan analyzer.