Synthesis of β-amino alcohol derivatives from phenols in presence of phase transfer catalyst and lipase biocatalyst

Article history: Received June 25, 2012 Received in Revised form November 6, 2012 Accepted 6 November 2012 Available online 6 November 2012 A simple and environmentally friendly reaction has been developed for the first time for onepot synthesis of β-amino alcohol derivatives from aromatic phenols, epichlorohydrin and amines by using phase transfer catalysts (PTC) and Aspergillus Oryzae lipase biocatalyst. This method provides access to pharmaceutically relevant products in excellent yields with high regioselectivity. The remarkable catalytic activity and reusability of lipase was possible up to four consecutive cycles. © 2013 Growing Science Ltd. All rights reserved.


Introduction
The β-Amino alcohols are present in many biologically active natural products and chiral auxiliaries containing common intermediates [1][2][3] .They play an increasingly important role in medicinal chemistry, pharmaceuticals and in organic synthesis [4][5] .β-Adrenergic blocking agents (βblockers) are used in treatment of a wide variety of human disorders like hypertension, sympathetic nervous system, heart failure, cardiac arrhythmias [6][7] and also as insecticidal agents 8 .
The skeleton of β-amino alcohols of the type 1 (Fig. 1) is particularly interesting in biologically active pharmaceutical compounds, which are easily available via one-pot multicomponent reaction process.Compounds such as propranolol 2 are used as selective dopamine D 4 receptor antagonists 9 .Pchelka et al. 19 reported the reaction of phenol and epichlorohydrin under microwave irradiation by using PTC like tetrabutylammonium bromide (TBAB).The role of PTC is to facilitate the reaction by migrating a reactant from one phase to another 29 .Commonly used PTCs are the salts of quaternary ammonium or phosphonium compounds, benzyl trimethyl ammonium chloride and TBAB 30 .Recently ionic liquids (ILs) which are known as environmentally benign and reusable reagents have attracted growing attention due to their high thermal stability [31][32][33] ILs based on 1,3dialkylimidazolium cation and pyridine cation are composed of cation/anion combinations, which are similar to the conventional quaternary ammonium salts and hence such type of ILs have the potential for use as PTC [34][35][36] .
We herein report the synthesis of pharmaceutically relevant β-amino alcohol derivatives in onepot reaction along with aromatic phenols, epichlorohydrin and amines by using lipase biocatalyst from Aspergillus Oryzae along with PTC.

Results and Discussion
The synthesis of β-amino alcohol derivatives using Aspergillus Oryzae lipase biocatalyst and PTC has been shown in Scheme 1.
The reaction between phenol (1a), epichlorohydrin and amine 2a was selected as a model reaction for optimizing the reaction parameters such as molar ratio, effects of solvents, catalyst study, catalyst amount, and reusability.As shown in Table 1, entries 1, 2, 3 we carried out the model reaction using different PTC such as triethylamine hydrochloride (TEA.HCl), TBAB and choline chloride.It was observed that the yield of product decreases respectively.The reaction using [BMIM]Cl as PTC gave maximum product yield with less reaction time (Table 1, entry 5, 6).This was attributed to small inorganic anion and bulky organic cation of [BMIM]Cl having high stability as compared to choline chloride, TEA.HCl and TBAB.Because the positive charge in [BMIM]Cl is delocalized over two nitrogen atoms and three carbon atoms, it imparts maximum resonance stability as compared to other tetraalkylammonium salts 37,38 .
For further optimization of [BMIM]Cl, the reaction was carried out with different quantities and 0.1 equivalent of [BMIM]Cl with respect to 1a was found to be optimal (Table 1, entries 4, 5, 6).In the absence of PTC, the product 3a was afforded in 30% yield after reaction at 55 º C for 8 h (Table 1, entry 7).For comparison, synthesis of β-amino alcohol derivatives was also studied using conventional bases such as sodium hydroxide 19 (NaOH), sodium hydride 21 (NaH), potassium carbonate (K 2 CO 3 ) and sodium bicarbonate (NaHCO 3 ) (Table 2, entries 1-4).These conventional bases required more reaction time while giving lower product yields.The reaction using Aspergillus Oryzae lipase biocatalyst (10% w/w) gave the product 3a in 60 % yield in 4 h.Further, excellent results were obtained by using 50% w/w lipase to afford the product 3a in 86 % yield in 3.5 h (Table 2, entries 5, 6).Use of NaHCO 3 or K 2 CO 3 as a base in the presence of lipase (10% w/w) as a biocatalyst obtained the product 3a in 87-88% yield after reacting at 55 º C for 3.5 h (Table 2, entries 7, 8), since the reaction is promoted by lipase and the base serves to trap the resulting hydrochloric acid which is a byproduct of the reaction.In the absence of base, lipase should work as a promoter as well as a captor of the acid.K 2 CO 3 and NaHCO 3 exhibited similar effect on reaction, although among the two, K 2 CO 3 gave higher product yield as it is more thermally stable and the conjugate base of K 2 CO 3 is more basic than that of NaHCO 3  19, 20 .No reaction could occur at room temperature (35 º C) in the presence of lipase.Reaction also did not occur in the absence of any catalyst.
Lipase biocatalysts are made up of different subunits having high efficiency and selectivity.Therefore, lipase biocatalysts can be used in a variety of organic transformations without the need of additional coenzymes 26 .Different organic solvents were also screened to see their efficiency in the reaction.Lipase is a heterogeneous catalyst and could easily separate from reaction mixture by filtration.
With these results in hand, we developed the one-pot synthesis of β-amino alcohol derivatives from various substituted aromatic phenols (1a-l), epichlorohydrin and amines (2a-l) to obtain the corresponding products (3a-l) (Table 3).The rate of reaction and product yield was better in case of secondary amines such as morpholine, piperidine compared to primary aliphatic amines like methyl amine, isopropyl amine, isobutyl amine, etc 39 .
The basicity of amine is expected to increase with the number of alkyl groups on the amine.In secondary amine, two alkyl groups are attached directly to the nitrogen atom resulting in better reactivity of the secondary amine as compared to the primary amine.Basicity also depends on stabilization of the conjugate acid formed and the conjugate acid of secondary amine was more stable than primary amine 39 .In 4-nitrophenol and 4-cyanophenol, due to the presence of electron withdrawing group at para position 20,40 after formation of phenoxide ion, the loan pair of electron gets stabilized by resonance and hence less available for nucleophilic attack with epichlorohydrin.Therefore, the reaction required more time (Table 3, entries i-l).In 2-chlorophenol, due to the presence of chloro group at ortho position the steric hindrance affects the reaction between phenol and epichlorohydrin, thereby requiring longer reaction time (Table 3, entries f, g).Phenol and its derivatives with electron donating substituents react faster as compared to phenol with electron accepting substituents.Also, the sterically hindered phenol reacts very slowly.
There are two possible ways of nucleophilic attack with different amines at the epoxide carbon, one at terminal carbon atom to form regioisomer A and another at internal carbon atom to form regioisomer B (Table 3).We afforded A as the major regioisomer, because nucleophilc attack of amines takes place preferentially at the terminal carbon atom of epoxide than internal carbon atom.Regioselectivity was determined by NMR spectrum.Regioisomer A has secondary alcohol group and carbon attached to that hydroxyl group gives chemical shift at δ = 68 ppm which we obtained in 13 C NMR spectrum of products, while, regioisomer B has primary alcohol group and carbon atom adjacent to it shows shift at δ = 60 ppm, which was not observed.Thus, the conclusion was that we obtained regioisomer A 39 .During the recyclability study of the lipase biocatalyst, it was easily separated from the reaction mass by filtration and was recycled up to four times.No significant decrease in the product yield was observed during the first recycle whereas the yield declined up to 70 % after completion of fourth recycle as shown in the Table 4.
Based on the observations, the mechanism for the reaction may be postulated as shown in Scheme 2. The active sites of lipase such as aspartate histidine dyad and oxyanion hole, abstract the acidic proton of the phenols 1a-l to form the nucleophiles X 41,42 A plausible reaction mechanism for the formation of β-amino alcohol derivatives 3a-l.
The FT-IR spectra of synthesized compounds showed the stretching frequency at 1250 and 1040 cm -1 clearly indicating the presence of ether linkage.Products were purified by column chromatography in 100-200 mesh silica.The product gave a single spot on TLC plate.All the synthesized compounds were characterized by 1 H-NMR, 13 C-NMR and FT-IR spectral data.

General procedure for synthesis of β-amino alcohols derivatives:
A mixture of phenols 1a-l (2 mmol), epichlorohydrin (3 mmol), lipase (10% w/w), [BMIM]Cl (0.2 mmol) and K 2 CO 3 (2 mmol) was stirred in 25 ml round bottom flask at 55 º C till the consumption of phenol (confirmed by TLC).Amine 2a-l (2 mmol) was then added in one portion to same reaction mixture and stirred at 55 º C to complete the reaction.The progress of the reaction was monitored by TLC.After completion of the reaction, it was then cooled to room temperature, then added ethyl acetate (10 ml) and water (10 ml).
Lipase was then filtered and then ethyl acetate layer was separated from water layer.It was dried by using anhydrous Na 2 SO 4 and concentrated in high vacuum to give the final crude product.Products were purified by column chromatography on 100-200 mesh silica compound eluted in ethyl acetate:hexane (6:4) to afford the pure final product.The separated lipase was washed with water, dried at room temperature and reused for the same reaction.

General procedure for synthesis of 1-butyl-3-methylimidazolium chloride 43 ([BMIM]Cl):
A mixture of 1-methylimidazole (1mmol) and butyl chloride (1.2 mmol) were stirred in round bottom flask fitted with a reflux condenser.The reaction mixture was refluxed for 12 h at 120 º C with constant stirring to complete the reaction by TLC.After completion, the reaction mass was cooled to room temperature, and the unreacted starting material was removed by distillation in high vacuum at 70 º C and 300 atm pressure to get final [BMIM]Cl.It was used as PTC in synthesis of β-amino alcohols derivatives.

Table 1 .
Effect of PTC on product yield 3a

Table 3 .
Synthesis of β-amino alcohol derivatives , which replace the Cl -of [BMIM]Cl giving the intermediate Y.It reacts with epichlorohydrin to give the intermediate Z. Sequential attack of the amines 2a-l on the intermediate Z gives the final products 3a-l.
13 C