Synthesis and Recovery of Pyridine- and Piperidine-based Camphorsulfonamide Organocatalysts Used for Michael Addition Reaction

Two new pyridine-based asymmetric bifunctional organocatalysts containing one or two camphorsulfonamide units were synthesized. Asymmetric Michael addition of pentane-2,4-dione to β-nitrostyrene was catalyzed by these organocatalysts. During our experiments, influence of the solvent and temperature on the yield and enantioselectivity was studied. Using monocamphorsulfonamide derivative the S enantiomer of the corresponding Michael adduct was gained with moderate yield (up to 51 %) and low enantiomeric excess (up to 18 %). Organic solvent nanofiltration was successfully applied for the recovery of these organocatalysts. Furthermore, pyridine camphorsulfonamide was reduced to its piperidine derivative. Using piperidine monosulfonamide derivative racemic Michael adduct was obtained with excellent yield (up to 89 %). Beside its organocatalytic relevance, piperidine monosulfonamide derivative may also possess biological activity.


Introduction
Undoubtedly, using a catalytic amount of chiral controller is an elegant and economically attractive way to introduce chirality into a molecule.Among enantioselective reactions, methods based on metal-free chiral organocatalysts have become more significant [1][2][3].We can state that asymmetric organocatalysis is one of the most rapidly growing research areas in synthetic organic chemistry [4,5].
The application of camphor derivatives in asymmetric organic reactions is a well-known method for chirality transfer.Camphor is one of nature's privileged scaffolds, readily available in both stereoisomers, and it can be easily altered to provide a wide range of optically active compounds [6].As important members of the camphor family, camphorsulfonamides were applied first as chiral auxiliaries [7][8][9][10], later as enantioselective organocatalysts [11][12][13][14][15][16].One of these reactions is the organocatalytic asymmetric Michael reaction, which is a powerful synthetic method to generate new carbon-carbon bond with concomitant formation of a new stereogenic center [17][18][19][20][21][22][23].Therefore, it can be applied in the synthesis of biologically important pharmaceuticals and chiral precursors for the synthesis of bioactive compounds (Fig. 1).[24][25][26] Recently Huang et al. [15] prepared camphorsulfonamide type organocatalysts and they demonstrated that the camphorsulfonamide group can enhance the effectiveness of asymmetric Michael reaction.Beside their potential organocatalytic activity, piperidine-based camphorsulfonamides may have biological activity.[27,28] The potential for realizing synergies based on combining membrane separations with chemical processing in industry is expanding with the development of solvent-resistant nanofiltration membranes.Organic solvent nanofiltration (OSN) is an emerging technology that allows separation of solutes between 50 and 2000 g•mol -1 via pressure gradient [29].OSN processes are considered to be sustainable, and there are recent attempts to improve the greenness of membrane fabrication as well with the overall aim to improve the life cycle assessment (LCA) of the field [30,31].Consequently, OSN is an attractive approach for process intensification via soluble catalyst recovery [32,33], pharmaceutical purification [34,35], and iterative synthesis [36,37].
Recently, we presented a preliminary study for the potential application of nanofiltration in the purification and recovery of crown ethers [38] and cinchona organocatalysts [39].In continuation of these studies, our attention turned to the recycling of other types of catalysts.This article presents a preliminary study for exploring the potential of OSN in the recovery of camphorsulfonamide-based organocatalysts.Regarding these results, we are focusing on introducing some new, easily accessible bifunctional pyridine and piperidine-camphorsulfonamide-type organocatalysts, which can be recovered by OSN.To study the catalytic activity of enantiopure camphorsulfonamide derivatives, we apply them in asymmetric Michael addition reaction.Moreover, piperidine-based camphorsulfonamide is among the potential bioactive compounds with high pharmaceutical relevance.
Note: In our reactions we used a chlorinated solvent (DCM), but tert-butyl methyl ether, 2-methyltetrahydrofuran or dimethyl carbonate should be used instead.Experiments are in progress to change DCM to green solvents, and results will be published as soon as the work on it is finished.

Materials
Starting materials were purchased from Aldrich Chemical Company.Silica gel 60 F 254 (Merck) plates were used for TLC.Silica gel 60 (70-230 mesh, Merck) were used for column chromatography.Ratios of solvents for the eluents are given in volumes (mL•mL -1 ).Evaporations were carried out under reduced pressure.

Synthesis and application of new, enantiopure pyridine-camphorsulfonamide derivatives
Our aim was to prepare new camphorsulfonamide derivatives as potential bifunctional organocatalysts.The simultaneous activation of the electrophile by the hydrogen bond donor sulfonamide unit and the nucleophile by the Brønsted basic group (pyridine nitrogen) together with the chiral camphor-skeleton, should provide enough interaction between the reactants and the organocatalyst to accomplish enantioselective reactions.
New organocatalysts (S)-1 and (S,S)-2 were used in the Michael addition of pentane-2,4-dione (6) to β-nitrostyrene (7) (Table 1).The reactions were carried out in five different solvents using 30 mol% catalyst.Compound (S,S)-2 showed no catalytic activity.Using (S)-1 as a catalyst at room temperature, both the yield and the enantiomeric excess were low.Increasing the temperature to 50 °C resulted in a small (MTBE, toluene) or significant (CH 3 CN) improvement in the yield, while the enantioselectivity of the reaction remained low.

Catalyst recovery via nanofiltration
Preliminary studies were carried out to evaluate the feasibility of OSN for recovery of camphorsulfonamides (S)-1 and (S,S)-2.Membranes were fabricated based on recently established method [41,42].Polybenzimidazole membranes (18 wt% and 22 wt% denoted as 18 PBI and 22 PBI) crosslinked with α,α'-dibromo-p-xylene were used for the filtration studies.Solutes were dissolved in  The nanofiltration was carried out in cross-flow configuration with 100 L•h -1 recirculation at 30 bar (Fig. 4).Permeate flux was measured and permeate and retentate samples were taken at steady state after approximately 4 h of continuous operation.Solvent fluxes (F) and solute rejections (R) were calculated as given in Eq. ( 1) 3 and Eq. ( 2) 4 , respectively: (1) The experimental rejections obtained for (S)-1 and (S,S)-2 in THF, IPA and toluene 5 at 30 bar using 18 PBI and 22 PBI are demonstrated in Fig. 5(A).The corresponding solvent fluxes are shown in Fig. 5(B).
As expected, the tighter membranes (22 PBI) have higher camphorsulfonamide rejection but lower flux values.Due to the larger molecular weight, (S,S)-2 has higher rejection compared to (S)-1 in all the tested solvents and membranes.The obtained rejection values also reveal that the rejection difference between the sulfonamides is smaller for the tighter membranes irrespectively of the solvent.The catalyst rejections vary between 48 % and 99 %.Efficient recovery necessitates rejections of virtually 100 %.Consequently, both IPA and THF can be used for nanofiltration with 22 PBI featuring a modest  Nanofiltration processes are usually operated in diafiltration mode.Based on the experimentally obtained rejection values, Fig. 6 shows the simulated concentration profile of the compounds during single-stage diafiltration.These results confirm that OSN can be practically used for the recovery, only when rejections are > 98 %.Insufficient rejection leads to significant catalyst loss during single-stage nanofiltration process.For instance, 93 % rejection results in 50 % catalyst loss in 10 diavolume processing time.However, recent process advancement of the OSN field suggests that employing a threestage cascade configuration can address the inherent limitation of diafiltration processes: low yield and high solvent consumption [43][44][45][46].Moreover, solvent treatment of the PBI membranes could also enhance the process performance [47].OSN can be synergistically combined with adsorption processes to achieve better performance, i.e. improved yield or purity [48].Based on our preliminary nanofiltration results, we plan to enhance the organocatalyst recovery via cascade approach and hybrid processes.

Synthesis and application of new, enantiopure piperidine-camphorsulfonamide derivative
Considering the low reaction yields of the Michael reaction (Table 1) catalyzed by (S)-1, and the fact, that (S,S)-2 has not been eligible for the addition reaction, we assumed that K b of the basic pyridine nitrogen is not high enough.Thus, it is conceivable that if we increase the basicity of the corresponding nitrogen, then higher conversion could be achieved.Accordingly, we synthesized analogue piperidine derivative (S)-3 by catalytic hydrogenation of (S)-1 (Fig. 7) using our published method [38].
The newly prepared piperidine derivative (S)-3 was also applied in Michael addition reaction (Table 2).As a confirmation of our assumption, the reaction yields at room temperature were significantly higher than in case of catalyst (S)-1.
Increasing the temperature to 50 °C resulted in higher yields in toluene and DCM, while using MTBE or IPA provided a decrease in the amount of products due to appearance of side-products.The products isolated at both temperatures were practically racemic.The best yield (89 %) was achieved in acetonitrile at room temperature.
Since the size of compounds (S)-1 and (S)-3 are almost equivalent, presumably their rejection is also identical.
In consideration of the results of the catalyzed Michael reactions at room temperature, among the examined membrane separation combinations, IPA can be the appropriate solvent for recycling both organocatalysts.

Conclusion
The applications of three easily synthesized camphorsulfonamide organocatalysts [(S)-1, (S,S)-2 and (S)-3] in Michael addition reaction have been presented.However, using pyridine-monocamphorsulfonamide (S)-1 only moderate yield and low enantioselectivity were achieved.The piperidine-based (S)-3, thanks to its higher basicity, gave racemic Michael adduct with higher yield (up to 89 %).The effect of solvent and temperature was considered, using acetonitrile at room temperature resulted in the most effective transformation without appearance of side-products.
The feasibility of OSN for recovery of organocatalysts [(S)-1 and (S,S)-2] was also demonstrated.Both IPA and THF can be used for nanofiltration with 22 PBI membrane featuring modest and excellent fluxes, respectively.The hybrid process including the application and recovery of the new organocatalysts will be reported as soon as that work is finished.

3 F
: permeate flux, V P : volume of permeate, A m : membrane area, t: time 4 R x : rejection of compound x, c P,x : permeate concentration of compound x, c R,x : retentate concentration of compound x. 5 Solvent selection was based on their different chemical characteristic (ether, alcohol and aromatic compound), also, industrial utilization as solvent was considered.

Table 2
Michael Addition of acetylacetone to nitrostyrene catalyzed by (S)-3 a