Asymmetric Conjugate Addition of Ketones to Maleimides Organocatalyzed by a Chiral Primary Amine-Salicylamide

Enantioenriched substituted succinimides are interesting compounds, and their asymmetric organocatalytic synthesis by the conjugated addition of ketones to maleimides has been scarcely explored. This study shows the enantioselective conjugate addition of ketones to maleimides organocatalyzed by a simple primary amine-salicylamide derived from a chiral trans-cyclohexane-1,2-diamine, which provides the desired succinimides in good to excellent yields (up to 98%) and with moderate to excellent enantioselectivities (up to 99%).


Introduction
Succinimides are attractive targets in organic synthesis, as they are present in natural products and drug candidates [1][2][3][4][5][6][7] and can be transformed into other interesting compounds [8][9][10][11]. One of the most direct ways of preparing enantioenriched substituted succinimides is the organocatalytic enantioselective conjugate addition of carbon nucleophiles to maleimides [12]. Thus, using chiral organocatalysts containing tertiary amines, these carbon nucleophiles can be generated by the α-deprotonation of the acidic hydrogens of pro-nucleophiles, such as 1,3-dicarbonyl compounds [12]. The formed enolate can coordinate with the protonated amine and, if the organocatalyst bears an acidic moiety coordinating the maleimide employing a hydrogen bond, a close transition state can be produced, leading to an efficient enantioselective process. However, when aldehydes or ketones are used as pro-nucleophiles, α-deprotonation is difficult. Conjugate addition can occur by creating a transient nucleophilic enamine generated using primary or secondary amine-bearing chiral organocatalysts.
Recently, we have used the primary amine-salicylamide derived from chiral transcyclohexane-1,2-diamine 8 ( Figure 2) as an effective organocatalyst for the enantioselective conjugate addition of aldehydes to maleimides [40,45]. We report here that this organocatalyst can be effective in the much less common asymmetric addition of ketones to maleimides. Recently, we have used the primary amine-salicylamide derived from chiral transcyclohexane-1,2-diamine 8 ( Figure 2) as an effective organocatalyst for the enantioselective conjugate addition of aldehydes to maleimides [40,45]. We report here that this organocatalyst can be effective in the much less common asymmetric addition of ketones to maleimides.

Results and Discussion
The search for the most appropriate reaction conditions (Table 1) was carried out using the model conjugate addition reaction of cyclohexanone (9a) to N-phenylmaleimide (1a) (2/1 molar ratio). Thus, the reaction organocatalyzed by 8 (20 mol%) in toluene as a solvent at room temperature during 3 d afforded the corresponding substituted succinimide as a 76/24 mixture of diastereomers, the anti-major one 11aa in 94% ee. The absolute configuration of the succinimide was determined by comparing the elution order of the corresponding four isomers in chiral HPLC with those in the literature [46]. The use of other hydrocarbons as solvents did not provide better results (Table 1, entries 2 and 3). In addition, chlorinated solvents were employed (Table 1, entries 4-6), with dichloromethane providing the best diastereoselectivity (80/20) and enantioselectivity (99% ee) for the main diastereomer 11aa. On the other hand, ether solvents (Table 1, entries 7 and 8) provided considerably lower stereoselectivities, as did acetonitrile (Table 1, entry 9), alcohol solvents or water, and methanol had no reaction (Table 1, entries 10-12). Moreover, we were intrigued as to whether a longer reaction time would modify the final stereoselectivity for 11aa when using dichloromethane as the best solvent. However, when the reaction was performed in 5 d reaction time, the final diastereo-and enantioselectivity remained unaltered (Table 1,    Recently, we have used the primary amine-salicylamide derived from chiral transcyclohexane-1,2-diamine 8 ( Figure 2) as an effective organocatalyst for the enantioselective conjugate addition of aldehydes to maleimides [40,45]. We report here that this organocatalyst can be effective in the much less common asymmetric addition of ketones to maleimides.

Results and Discussion
The search for the most appropriate reaction conditions (Table 1) was carried out using the model conjugate addition reaction of cyclohexanone (9a) to N-phenylmaleimide (1a) (2/1 molar ratio). Thus, the reaction organocatalyzed by 8 (20 mol%) in toluene as a solvent at room temperature during 3 d afforded the corresponding substituted succinimide as a 76/24 mixture of diastereomers, the anti-major one 11aa in 94% ee. The absolute configuration of the succinimide was determined by comparing the elution order of the corresponding four isomers in chiral HPLC with those in the literature [46]. The use of other hydrocarbons as solvents did not provide better results (Table 1, entries 2 and 3). In addition, chlorinated solvents were employed (Table 1, entries 4-6), with dichloromethane providing the best diastereoselectivity (80/20) and enantioselectivity (99% ee) for the main diastereomer 11aa. On the other hand, ether solvents (Table 1, entries  7 and 8) provided considerably lower stereoselectivities, as did acetonitrile (Table 1, entry 9), alcohol solvents or water, and methanol had no reaction (Table 1, entries 10-12). Moreover, we were intrigued as to whether a longer reaction time would modify the final stereoselectivity for 11aa when using dichloromethane as the best solvent. However, when the reaction was performed in 5 d reaction time, the final diastereo-and enantioselectivity remained unaltered (Table 1,

Results and Discussion
The search for the most appropriate reaction conditions (Table 1) was carried out using the model conjugate addition reaction of cyclohexanone (9a) to N-phenylmaleimide (1a) (2/1 molar ratio). Thus, the reaction organocatalyzed by 8 (20 mol%) in toluene as a solvent at room temperature during 3 d afforded the corresponding substituted succinimide as a 76/24 mixture of diastereomers, the anti-major one 11aa in 94% ee. The absolute configuration of the succinimide was determined by comparing the elution order of the corresponding four isomers in chiral HPLC with those in the literature [46]. The use of other hydrocarbons as solvents did not provide better results (Table 1, entries 2 and 3). In addition, chlorinated solvents were employed (  [10][11][12]. Moreover, we were intrigued as to whether a longer reaction time would modify the final stereoselectivity for 11aa when using dichloromethane as the best solvent. However, when the reaction was performed in 5 d reaction time, the final diastereo-and enantio-selectivity remained unaltered (Table 1, compare entries 4 and 13).  Next, we explore the influence of adding additives to the reaction using dichloromethane as the best solvent. Thus, adding 10 mol% of different carboxylic acids as additives had a result detrimental to the stereoselectivity (Table 1, entries [14][15][16][17]. Moreover, the use of a 10 mol% of organic bases such as 4-(dimethylamino)pyridine (DMAP), imidazole, 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU), or 2,6-lutidine proved ineffective (Table 1, entries [18][19][20][21]. However, the use of 1,4-diazabicyclo[2.2.2]octane (DABCO) (10 mol%) as additive raised the anti/syn diastereomer ratio to 85/25, and the enantioselectivity for 11aa was 99% (Table 1, entry 22). The loading of DABCO was increased and lowered, however this was not beneficial in any case (Table 1, entries 23 and 24). Furthermore, the reaction temperature was reduced to 5 • C while keeping DABCO (10 mol%) as an additive in dichloromethane, resulting in a diastereomeric ratio of 93/7 favoring 11aa and a 99% ee (Table 1,  With the optimized reaction conditions in hand [8 (20 mol%), DABCO (10 mol%), CH 2 Cl 2 , 5 • C], we extended the procedure to other substrates (see Figure 3 and Table 2; see Figures S3-S42 and Figures S45-S84 in Supplementary Materials). We first explored the reaction of cyclohexanone (9a) with other N-substituted maleimides (10b-h) ( Figure 3 and Table 2). Thus, electron-releasing and electron-withdrawing groups on the aromatic ring of the N-arylated maleimide provided the corresponding major adducts 11ab-af ( Figure 3) with good diastereoselectivities and with moderate enantioselectivities ( Table 2, entries 2-6). In addition, when N-methyl or N-ethyl maleimide was used, the diastereoselectivity of the reaction for 11ag and 11ah was good, with similar enantioselectivities of 76 and 77% (  Figure 3. Products obtained in the conjugate addition of ketones to maleimides using 8 as organocatalyst. Only the major stereoisomer is represented; 4-O2NC6H4CO2H (10 mol%) was used as co-catalyst for adducts 11ba, 11ca, 11da and 11di. Compounds 11ba-11ga, 11di and 11gi were obtained at room temperature.
We extended this conjugate addition to other ketones. Thus, five-and sevenmembered cyclic ketones 9b-d reacted with N-phenylmaleimide (10a) to provide the corresponding major succinimides 11ba-da ( Figure 3), with rather a low diastereoselectivity but with an ee reaching 93% for 11ca using 2,2,dimethylcyclopentanone (9c) ( Table 2, entries 10-12). In these three cases, the presence . Products obtained in the conjugate addition of ketones to maleimides using 8 as organocatalyst. Only the major stereoisomer is represented; 4-O 2 NC 6 H 4 CO 2 H (10 mol%) was used as co-catalyst for adducts 11ba, 11ca, 11da and 11di. Compounds 11ba-11ga, 11di and 11gi were obtained at room temperature. We extended this conjugate addition to other ketones. Thus, five-and seven-membered cyclic ketones 9b-d reacted with N-phenylmaleimide (10a) to provide the corresponding major succinimides 11ba-da ( Figure 3), with rather a low diastereoselectivity but with an ee reaching 93% for 11ca using 2,2,dimethylcyclopentanone (9c) ( Table 2, entries 10-12). In these three cases, the presence of an acid additive such as p-nitrobenzoic acid proved superior to DABCO, working at room temperature being necessary to avoid very slow reactions.
Finally, and considering the good results obtained using the simple maleimide 10i as an electrophile, we explored the reaction with other ketones such as cycloheptanone (9d) and tetrahydro-4H-pyran-4-one (9g), obtaining the corresponding adducts 11di and 11gi, again with high enantioselections (Table 2, entries 20 and 21).
We scaled up the reaction leading to 11aa using 7.4 mmol of 9a and 3.7 mmol of 10a instead of 0.4 mmol of 9a and 0.2 mmol of 10a (see Materials and Methods). The corresponding adduct 11aa was obtained with a 97% ee (Table 2, entry 20).
Based on previous DFT calculations concerning the favorable transition states in the conjugated addition reaction of aldehydes to maleimides when using 8 [40], a suggested approach justifying the formation of 11aa is depicted in Figure 4. Here, 8 would act as a bifunctional species, forming a transient enamine and at the same time coordinating one of the carbonyl groups of the maleimide through a hydrogen bond involving the amide N-H in the organocatalyst.
Finally, and considering the good results obtained using the simple maleimide 10i as an electrophile, we explored the reaction with other ketones such as cycloheptanone (9d) and tetrahydro-4H-pyran-4-one (9g), obtaining the corresponding adducts 11di and 11gi, again with high enantioselections (Table 2, entries 20 and 21).
We scaled up the reaction leading to 11aa using 7.4 mmol of 9a and 3.7 mmol of 10a instead of 0.4 mmol of 9a and 0.2 mmol of 10a (see Materials and Methods). The corresponding adduct 11aa was obtained with a 97% ee (Table 2, entry 20).
Based on previous DFT calculations concerning the favorable transition states in the conjugated addition reaction of aldehydes to maleimides when using 8 [40], a suggested approach justifying the formation of 11aa is depicted in Figure 4. Here, 8 would act as a bifunctional species, forming a transient enamine and at the same time coordinating one of the carbonyl groups of the maleimide through a hydrogen bond involving the amide N-H in the organocatalyst.

General Information
Commercially available reagents (Acros Organics, Alfa Aesar, Fluorochem, Sigma Aldrich, TCI Chemicals) were used without further purification. 1 H NMR spectra were recorded on Bruker AV300 (300 MHz) and Bruker AV400 (400 MHz) spectrometers in proton coupled mode at room temperature. 13 C NMR spectra were recorded on Bruker AV300 (75 MHz) and Bruker AV400 (101 MHz) spectrometers in proton decoupled mode at room temperature. Chemical shifts (δ) are given in parts per million (ppm). CDCl3 was used as solvent and tetramethylsilane (TMS) as internal standard. Coupling constants (J) are given in Hz. Infrared (IR) spectra were recorded with an ATR Jasco FT/IR-4100 from neat samples. Wavenumbers (υ) are given in cm −1 and the intensity is provided as very strong (vs), strong (s), weak (w), or broad (br). High resolution mass spectrometry data were obtained on an Agilent 7200 Q-TOF (EI-QTOF) and on an Agilent 1260 Chip-HPLC in line with a mass spectrometer 6500 series Q-TOF (ESI-QTOF). Thin layer chromatography (TLC) was carried out on Macherey-Nagel Alugram Sil G UV254 aluminum sheets coated with a 0.2 mm layer of silica gel. A UV light lamp (254 nm) was employed for detection. Flash column chromatography was performed using silica gel 60 of 40-63 µ m (230-400 mesh) size. The ee's were determined on an Agilent 1100 Series

General Information
Commercially available reagents (Acros Organics, Alfa Aesar, Fluorochem, Sigma Aldrich, TCI Chemicals) were used without further purification. 1 H NMR spectra were recorded on Bruker AV300 (300 MHz) and Bruker AV400 (400 MHz) spectrometers in proton coupled mode at room temperature. 13 C NMR spectra were recorded on Bruker AV300 (75 MHz) and Bruker AV400 (101 MHz) spectrometers in proton decoupled mode at room temperature. Chemical shifts (δ) are given in parts per million (ppm). CDCl 3 was used as solvent and tetramethylsilane (TMS) as internal standard. Coupling constants (J) are given in Hz. Infrared (IR) spectra were recorded with an ATR Jasco FT/IR-4100 from neat samples. Wavenumbers (υ) are given in cm −1 and the intensity is provided as very strong (vs), strong (s), weak (w), or broad (br). High resolution mass spectrometry data were obtained on an Agilent 7200 Q-TOF (EI-QTOF) and on an Agilent 1260 Chip-HPLC in line with a mass spectrometer 6500 series Q-TOF (ESI-QTOF). Thin layer chromatography (TLC) was carried out on Macherey-Nagel Alugram Sil G UV254 aluminum sheets coated with a 0.2 mm layer of silica gel. A UV light lamp (254 nm) was employed for detection. Flash column chromatography was performed using silica gel 60 of 40-63 µm (230-400 mesh) size. The ee's were determined on an Agilent 1100 Series HPLC equipped with an Agilent G1311A quaternary pump and an Agilent G1315B diode array detector (DAD). The employed conditions (column, mobile phase, flow rate, wavelength) are shown in each case. Reference racemic samples of adducts 11 were obtained by performing the conjugate addition reactions using a racemic mixture of 8 and ent-8 as organocatalyst at room temperature.

Conclusions
We have demonstrated that a simple primary amine-salicylamide derived from chiral trans-cyclohexane-1,2-diamine acts as an appropriate organocatalyst for the diastereoand enantio-selective conjugate addition of ketones to maleimides, with the presence of an organic base such as 1,4-diazabicyclo[2.2.2]octane (DABCO) generally improving the stereoselectivity. Cyclic and acyclic ketones are used in this addition reaction with N-aryland N-alkyl-maleimides, usually affording the final succinimides in good yields. The stereoselectivity of the process ranges from low to very good in the case of diastereoselectivity and from moderate to excellent concerning enantioselectivity, even when using simple N-unsubstituted maleimide. This asymmetric procedure is an interesting alternative to the short array of methodologies leading to these substituted ketone-containing succinimides.