A simple and environmentally friendly reaction has been developed for the first time for one-pot 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.

Borude, V., Shah, R & Shukla, S. (2013). Synthesis of β-amino alcohol derivatives from phenols in presence of phase transfer catalyst and lipase biocatalyst.Current Chemistry Letters, 2(1), 1-12.

Current Chemistry Letters 2 (2013) 1–12Contents lists available at Growing Science

Current Chemistry Letters

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

Vasant S. Borude, Rikhil V. Shah and Sanjeev R. Shukla*

Dept. of Fibres and Textile Processing Technology, Institute of Chemical Technology (University under Section-3 of UGC Act 1956), Matunga, Mumbai 400019, India

C H R O N I C L E A B S T R A C T

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 one-pot 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.

Keywords:

Lipase, β-Amino Alcohol

Phase Transfer Catalyst Epichlorohydrin

Biocatalyst

1-Butyl-3-methylimidazolium Chloride Introduction

The β-Amino alcohols are present in many biologically active natural products and chiral auxiliaries containing common intermediates1-3. They play an increasingly important role in medicinal chemistry, pharmaceuticals and in organic synthesis4-5. β-Adrenergic blocking agents (β-blockers) are used in treatment of a wide variety of human disorders like hypertension, sympathetic nervous system, heart failure, cardiac arrhythmias6-7 and also as insecticidal agents8.

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 D4 receptor antagonists9.

Some β-amino alcohol derivatives 3 prove to be useful as antagonists of the calcium receptor I that inhibits parathyroid hormone secretagogues10, other compounds such as practolol 4 and celiprolol hydrochloride 5 are the drugs belonging to the class of arloxypropanolamine 1 useful as β-blocker11, 12.

One of the most common methods used for the synthesis of β-amino alcohols is the direct aminolysis of epoxides using different promoters or catalysts in the presence of conventional solvents. These include calcium trifluoromethanesulfonate13, ionic liquids14, bismuth triflate15, polymer-supported chiral Co(Salen) complexes16, copper(II) acetylacetonate (Cu(acac)2)17, microwave irradiation18, etc.

Synthesis of epoxide from phenol and epichlorohydrin by using different methods, catalysts and organic solvents includes microwave irradiation19, cesium fluoride20, sodium hydride21, cesium carbonate22 and β-cyclodextrin23 etc.

The emerging area of green chemistry makes use of safer and non toxic materials, leaves no waste to treat, increases energy efficiency, uses renewable feed stock, maximizes atom economy and minimizes the potential for accidents. Biocatalyst provides excellent alternative in organic synthesis. The lipases from Aspergilllus Oryzae as biocatalyst are well established in organic synthesis because of their stability, selectivity and easy availability24-25. The use of lipase is well known in Knoevenagel condensation26, Mannich reaction27, ester hydrolysis28, etc. However, its application in the one-pot synthesis of β-amino alcohol derivatives from aromatic phenols has not been well explored.



Fig. 1. General formula (1) and examples of biologically active (2-5) β-amino alcohols

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 another29. Commonly used PTCs are the salts of quaternary ammonium or phosphonium compounds, benzyl trimethyl ammonium chloride and TBAB30. Recently ionic liquids (ILs) which are known as environmentally benign and reusable reagents have attracted growing attention due to their high thermal stability31-33 ILs based on 1,3-dialkylimidazolium 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 PTC34-36.

We herein report the synthesis of pharmaceutically relevant β-amino alcohol derivatives in one-pot reaction along with aromatic phenols, epichlorohydrin and amines by using lipase biocatalyst from Aspergillus Oryzae along with PTC.

2. Results and Discussion

The synthesis of β-amino alcohol derivatives using Aspergillus Oryzae lipase biocatalyst and PTC has been shown in Scheme 1.



Scheme 1: General Reaction Scheme

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 salts37, 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 ºC for 8 h (Table 1, entry 7).

Table 1. Effect of PTC on product yield 3a

Entry.a PTC (equiv.) Time (h) Yield (%)

1 TEA.HCl (0.1) 5.5 55

2 TBAB (0.1) 6 46

3 Choline Chloride (0.1) 6.5 42

4 [BMIM] Cl (0.05) 6 41

5 [BMIM] Cl (0.1) 4 60

6 [BMIM] Cl (0.2) 4 60

7 - 8 30

Reaction Condition: All reactions were carried out with phenol 1a (2 mmol), epichlorohydrin (3 mmol), morpholine 2a (2 mmol), lipase (10% w/w, 0.019g), temperature (55 ºC), Isolated yields.

For comparison, synthesis of β-amino alcohol derivatives was also studied using conventional bases such as sodium hydroxide19 (NaOH), sodium hydride21 (NaH), potassium carbonate (K2CO3) and sodium bicarbonate (NaHCO3) (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 NaHCO3 or K2CO3 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 ºC 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. K2CO3 and NaHCO3 exhibited similar effect on reaction, although among the two, K2CO3 gave higher product yield as it is more thermally stable and the conjugate base of K2CO3 is more basic than that of NaHCO319, 20. No reaction could occur at room temperature (35 ºC) 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 coenzymes26. 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, etc39.

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 amine39.

Table 2. Effect of catalyst, Base and solvent on product yield 3a

Entry Catalyst Base (1 equiv.) Solvent Temp.

(ºC) Time (h) Yield (%)

1 - NaOH - 55 20 40

2 - NaH - 55 12 55

3 - K2CO3 - 55 15 30

4 - NaHCO3 - 55 18 25

5 Lipase (10% w/w) - - 55 4 60

6 Lipase (50% w/w) - - 55 3.5 86

7 Lipase(10% w/w) NaHCO3 - 55 3.5 87

8 Lipase (10% w/w) K2CO3 - 55 3.5 88

9 Lipase (10% w/w) K2CO3 - 110 3 35

10 Lipase (10% w/w) K2CO3 DMF 55 6 60

11 Lipase (10% w/w) K2CO3 Dioxane 55 8 50

12 Lipase (10% w/w) K2CO3 THF 55 7 55

Reaction Condition: All reactions were carried out with phenol 1a (2 mmol), epichlorohydrin (3 mmol), amine 2a (2 mmole), [BMIM]Cl (0.035g, 0.1 equiv.), Isolated yields.

In 4-nitrophenol and 4-cyanophenol, due to the presence of electron withdrawing group at para position20, 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).

Table 3. Synthesis of β-amino alcohol derivatives



Entry ArOH Amine Product A Time (h) Yield (%)

3.5 88

4.5 82

5 80

D 4 75

E 5 72

F 5.5 83

G 6 78

h 4.5 73

I 5.5 68

J 6 71

K 8 60

L 7 82

Reaction Condition: All reactions were carried out with phenol 1a-l (2 mmol), epichlorohydrin (3 mmol), amine 2a-l (2 mmol), lipase (10% w/w), [BMIM]Cl (0.1 equiv.), K2CO3 (1 equiv.), Isolated yields. Regioselectivity was determined by NMR spectra.

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 13C 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 A39. 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 X41, 42, 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.

Table 4. Recyclability study of Lipase on product yield 3a

Entry Recycle Yield (%)

1 - 88

2 First 85

3 Second 80

4 Third 78

5 Fourth 70

Reaction Condition: All reactions were carried out with phenol 1a (2 mmol), epichlorohydrin (3 mmol), amine 2a (2 mmole), [BMIM]Cl (0.035g, 0.1 equiv.), K2CO3 (1 equiv.), Isolated yields.



Scheme 2. 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 1H-NMR, 13C-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 K2CO3 (2 mmol) was stirred in 25 ml round bottom flask at 55 ºC 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 ºC 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 Na2SO4 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 chloride43 ([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 ºC 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 ºC and 300 atm pressure to get final [BMIM]Cl. It was used as PTC in synthesis of β-amino alcohols derivatives.

Spectra data

1-Morpholino-3-phenoxypropan-2-ol, Table-3, Entry 3a:

A yellowish brown colored liquid.FT-IR (neat, cm–1): 3402, 2923, 2858, 1593, 1492, 1456, 1240, 1110, 1039, 865, 802, 754, 688.

1H NMR (300 MHz, CDCl3): 2.35-2.75 (m, 6H), 3.60-3.80 (m, 5H), 3.98 (d, 2H, J = 5.1Hz), 4.10 (m, 1H), 6.88-7.00 (q, J = 7.2 Hz, 7.5Hz, 2H), 7.22-7.34 (q, J = 7.2 Hz, 7.8 Hz, 8.4 Hz, 3H).

13C NMR (75 MHz, CDCl3): δ (ppm) 53.8, 61.1, 65.5, 66.9, 70.1, 114.5, 121.0, 129.5, 158.6.

1-Morpholino-3-(naphthalen-1-yloxy)propan-2-ol, Table-3, Entry 3b:

A yellow colored liquid.FT-IR (neat, cm–1): 3413, 2925, 2858, 1583, 1452, 1396, 1269, 1105, 1008, 864, 779.

1H NMR (300 MHz, CDCl3): 2.40-3.05 (m, 7H), 3.65-3.85 (m, 4H), 4.05-4.35 (m, 3H), 6.82 (d, J = 7.5 Hz, 1H), 7.32-7.54 (m, J = 3.9 Hz, 5.4 Hz, 7.2 Hz, 4H), 7.80 (dd, J = 3.3 Hz, 7.2 Hz, 1H), 8.26 (t, J = 5.4 Hz, 7.2 Hz, 9.6Hz, 1H).

13C NMR (75 MHz, CDCl3): δ (ppm) 53.7, 61.3, 65.6, 66.9, 70.4, 104.8, 120.6, 121.8, 125.2, 125.5, 125.8, 126.4, 127.5, 134.4, 154.3.

1-(Isopropylamino)-3-(naphthalen-1-yloxy)propan-2-ol, Table-3, Entry 3c:

A yellow colored liquid.FT-IR (neat, cm–1): 3328, 3056, 2962, 1581, 1454, 1394, 1269, 1099, 761.

1H NMR (300 MHz, CDCl3): 1.05 (d, 6H), 2.65-2.95 (m, 2H), 3.05 (m, 1H), 3.85 (bs, 1H), 4.10 (d, 2H, J = 4.8 Hz), 4.21 (m, 1H), 6.74 (q, J = 7.5 Hz, 7.8 Hz, 10.8 Hz, 1H), 7.26-7.50 (m, J = 1.5 Hz, 6.6 Hz, 7.8 Hz, 9.3 Hz, 10.8 Hz, 4H), 7.76 (t, J = 9.3 Hz, 1H), 8.24 (t, J = 6.6 Hz, 9.3 Hz, 1H).13C NMR (75 MHz, CDCl3): δ (ppm) 18.2, 19.9, 52.7, 53.6, 68.6, 70.3, 104.9, 120.6, 121.8, 125.3, 125.5, 125.9, 126.4, 127.5, 134.5, 154.3.

1-(Piperidin-1-yl)-3-(m-tolyloxy)propan-2-ol, Table-3, Entry 3d:

A yellowish orange colored liquid.FT-IR (neat, cm–1): 3396, 2931, 2796, 1595, 1483, 1448, 1259, 1161, 1043, 993, 935, 864, 775, 686.

1H NMR (300 MHz, CDCl3): 1.32-1.64 (m, 6H), 2.26 (s, 3H), 2.26-2.64 (m, 6H), 3.66 (bs, 1H), 3.89 (d, 2H, J = 5.1Hz), 4.02 (m, 1H), 6.63-6.74 (t, J = 1.2 Hz, 7.2 Hz, 9.3 Hz, 3H), 7.09 (t, J = 1.2 Hz, 3 Hz, 1H).

13C NMR (75 MHz, CDCl3): δ (ppm) 21.4, 24.1, 25.9, 54.7, 61.3, 65.4, 70.3, 111.3, 115.3, 121.6, 129.1, 139.3, 158.7.

1-(Methylamino)-3-(m-tolyloxy)propan-2-ol, Table-3, Entry 3e:

A yellowish brown colored liquid.FT-IR (neat, cm–1): 3375, 2916, 2804, 1595, 1452, 1257, 1161, 1043, 931, 867, 773, 686.

1H NMR (300 MHz, CDCl3): 2.28 (s, 3H), 2.36 (d, 1H), 2.50-2.74 (m, 4H), 3.50 (bs, 1H), 3.91 (d, 2H, J = 5.7 Hz), 4.08 (m, 1H), 6.64-6.80 (q, J = 7.8 Hz, 8.1 Hz, 9.3 Hz, 3H), 7.08-7.17 (t, J = 7.8 Hz, 8.1 Hz, 1H).

13C NMR (75 MHz, CDCl3): δ (ppm) 21.5, 42.9, 60.5, 67.4, 70.1, 111.4, 115.4, 121.8, 129.2, 139.5, 158.6.

1-(2-Chlorophenoxy)-3-morpholinopropan-2-ol, Table-3, Entry 3f:

A brown colored liquid.FT-IR (neat, cm–1): 3407, 2950, 2815, 1585, 1481, 1450, 1284, 1244, 1112, 1062, 865, 750, 692.

1H NMR (300 MHz, CDCl3): 2.42-2.72 (m, 6H), 3.38 (s, 1H), 3.64-3.78 (m, 4H), 4.04 (d, 2H, J = 4.8 Hz), 4.14 (m, 1H), 6.85-6.98 (m, J = 1.5 Hz, 6.9 Hz, 7.5 Hz, 7.8 Hz, 2H), 7.19 (m, J = 1.8 Hz, 6.6 Hz, 7.5 Hz, 7.8 Hz, 1H), 7.34 (dd, J = 1.5 Hz, 1.8 Hz, 6.0 Hz, 7.5 Hz, 7.8 Hz, 1H).13C NMR (75 MHz, CDCl3): δ (ppm) 53.7, 60.9, 65.6, 66.8, 71.3, 113.7, 121.7, 122.9, 127.7, 130.2, 154.1.

1-(2-Chlorophenoxy)-3-(isopropylamino)propan-2-ol, Table-3, Entry 3g:

A yellow colored liquid.FT-IR (neat, cm–1): 3357, 2962, 2877, 1585, 1477, 1245, 1056, 1027, 935, 813, 746, 690

1H NMR (300 MHz, CDCl3): 1.05 (d, 6H), 2.60-2.90 (m, 2H), 3.05 (m, 1H), 3.85-4.15 (m, 4H), 6.83-6.96 (m, J = 1.5 Hz, 7.5 Hz, 7.8 Hz, 9.6 Hz, 2H), 7.17 (t, J = 1.8 Hz, 7.2 Hz, 7.5 Hz, 8.4 Hz, 9.3 Hz, 1H), 7.33 (dd, J = 1.5 Hz, 7.8 Hz, 9.3 Hz, 1H).

13C NMR (75 MHz, CDCl3): δ (ppm) 17.9, 19.5, 52.7, 53.3, 68.2, 70.9, 113.7, 121.7, 122.8, 127.7, 130.1, 154.0.

1-(4-Bromophenoxy)-3-(methylamino)propan-2-ol, Table-3, Entry 3h:

A yellow colored liquid.FT-IR (neat, cm–1): 3386, 2933, 2804, 1585, 1483, 1236, 1033, 881, 815, 690.

1H NMR (300 MHz, CDCl3): 2.38 (d, 1H), 2.52-2.74 (m, 4H), 3.44 (bs, 1H), 3.90 (d, 2H, J = 4.8 Hz), 4.10 (m, 1H), 6.76 (dd, J = 2.1 Hz, 6.9 Hz, 8.1 Hz, 2H), 7.35 (dd, J = 1.8 Hz, 6.9 Hz, 8.7 Hz, 2H).

13C NMR (75 MHz, CDCl3): δ (ppm) 42.8, 60.2, 67.2, 70.3, 113.2, 116.3, 132.2, 157.6.

4-(2-Hydroxy-3-(isopropylamino)propoxy)benzonitrile, Table-3, Entry 3i:

A yellow colored liquid.FT-IR (neat, cm–1): 3404, 2962, 2358, 2223, 1602, 1504, 1458, 1253, 1170, 1101, 1022, 831, 715.

1H NMR (300 MHz, CDCl3): 1.06 (d, J = 6.6 Hz, 6H), 2.56-2.84 (m, 2H), 3.00 (m, 1H), 3.46 (bs, 1H), 3.96-4.14 (m, 3H), 6.96 (dd, J = 1.8 Hz, 2.1 Hz, 6.9 Hz, 9 Hz, 2H), 7.56 (dd, J = 1.8 Hz, 2.4 Hz, 6.9 Hz, 9.6 Hz, 2H).

13C NMR (75 MHz, CDCl3): δ (ppm) 18.1, 19.8, 52.3, 52.9, 68.1, 70.4, 103.9, 115.2, 119.0, 133.9, 161.9.

4-(3-(t-Butylamino)-2-hydroxypropoxy)benzonitrile, Table-3, Entry 3j:

A white solid.MP: 99-101ºC

FT-IR (neat, cm–1): 3132, 2925, 2860, 2219, 1596, 1500, 1251, 1120, 1016, 916, 837, 707.

1H NMR (300 MHz, CDCl3): 1.14 (s, 9H), 2.70 (m, 1H), 2.86(dd, 1H), 3.46(bs, 1H), 4.05 (m, 3H), 6.98 (dd, J = 2.1 Hz, 6.6 Hz, 8.7 Hz, 2H), 7.57 (dd, J = 2.1 Hz, 6.9 Hz, 8.7 Hz, 2H).

13C NMR (75 MHz, CDCl3): δ (ppm) 28.6, 28.8, 44.6, 50.9, 68.0, 70.7, 104.1, 115.3, 119.1, 133.9, 162.0.

1-(t-Butylamino)-3-(4-nitrophenoxy)propan-2-ol, Table-3, Entry 3k:

A yellowish orange colored liquid.FT-IR (neat, cm–1): 3299, 2964, 1593, 1506, 1334, 1259, 1107, 1020, 850, 750, 690.

1H NMR (300 MHz, CDCl3): 1.15 (s, 9H), 2.75 (q, 1H), 2.90(dd, 1H), 4.00-4.15 (m, 3H), 4.25 (bs, 1H), 6.98 (dd, J = 1.8 Hz, 6.9 Hz, 9Hz, 2H), 8.18 (dd, J = 1.8 Hz, 7.2 Hz, 9.3 Hz, 2H).

13C NMR (75 MHz, CDCl3): δ (ppm) 28.5, 44.6, 51.3, 67.9, 71.2, 114.5, 125.8, 141.5, 163.7.

1-Morpholino-3-(4-nitrophenoxy)propan-2-ol, Table-3, Entry 3l:

A white solid.MP: 78-80ºC

FT-IR (neat, cm–1): 3271, 2937, 2827, 1587, 1498, 1330, 1253, 1105, 989, 898, 850, 748.

1H NMR (300 MHz, CDCl3): 2.44-2.76 (m, 6H), 3.32 (s, 1H), 3.68-3.82 (m, 4H), 4.02-4.20 (m, 3H), 7.00 (dd, J = 2.1 Hz, 3.3 Hz, 6.9 Hz, 7.2 Hz, 9.3 Hz, 2H), 8.19 (dd, J = 2.1 Hz, 3.3 Hz, 7.2 Hz, 9.3 Hz, 2H).

13C NMR (75 MHz, CDCl3): δ (ppm) 53.7, 60.7, 65.1, 66.8, 70.9, 114.5, 125.8, 141.6, 163.7.

Acknowledgments

The Authors are thankful to University Grant Commission (UGC-SAP programme) INDIA for financial assistance to Mr. Vasant S. Borude and Mr. Rikhil V. Shah.

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