CHAPTER 5. Green Chemistry Approach to Aromatic Nucleophilic Substitution reactions: Formal synthesis of Linezolid

Transcription

1 190 CHAPTER 5 Green Chemistry Approach to Aromatic ucleophilic Substitution reactions: ormal synthesis of Linezolid

2 Introduction Aromatic nucleophilic substitution reaction is one of the useful and key chemical transformations in organic chemistry 1. The broad mechanistic classes that can be recognized include additionelimination 2a, elimination-addition 2b, metal-catalyzed 2c and radical or electron-transfer processes 2d. Particularly, the addition elimination mechanism predominates in nitro aromatic compounds and is extensively used in the synthesis of several biologically active molecules like eperezolid 1 3a, linezolid 2 3b, and ranbezolid 3 3c, Chart Chart-5.1 Aromatic nucleophilic substitution reactions generally demand strong electron-withdrawing groups on the aromatic ring and a potential leaving group present at the carbon at which the nucleophilic addition occurs. Metal salts consisting of alkali metal cations and certain anions are traditional nucleophile sources in the nucleophilic substitution

3 192 processes. ne classical reaction is the Chichibabin reaction, in which pyridine is reacted with an alkali-metal amide such as sodium amide to give 2-aminopyridine. These metal salts are generally stable, economical and easy to obtain. However, their limited solubility and low nucleophilicity in organic solvents make the processes of nucleophilic substitution reaction difficult. Generally, the polar aprotic solvents, 4 particularly dimethyl sulfoxide (DMS), hexamethylphosphoric triamide (HMPA) and -methyl pyrrolidinone (MP), etc. are good solvents for nucleophilic aromatic substitution reactions using metal salts. However, higher water solubility of these solvents and their high boiling points create problems in the separation and purification of the product. In 2003 Dae Yoo Chi et al. 5 described a highly efficient method for the nucleophilic fluorination of alkyl mesylate or alkyl halide to generate fluoroalkanes using K in the presence of an ionic liquid such as [bmim] [X] -, Scheme-5.1. The ionic liquid not only enhanced the reactivity of K significantly, but also reduced the formation of byproducts such as alkenes and/or alcohol. 4 MS 5 equiv M, C CH 3 C (5% H 2 ) [bmim] [B 4 ] 5 Scheme: 5.1 luorination of mesylate with metal fluoride in [bmim] [B4].

4 193 Aryl amines are very common structural compounds in biologically active natural products, medicinally important compounds, as well as in materials with useful electrical and mechanical properties. 6 Substituted aryl amines are widely used clinically as anti histaminic, anti hypertensive and anti inflammatory drugs. They are also an important class of compounds in neuropharmaceuticals. 7 ucleophilic aromatic substitution reactions have become very useful for introducing amine functionality to a benzene ring. 8 Classical methods for the synthesis of aryl amines typically require a large excess of base, highly polar solvents such as DM and DMS at higher temperatures with highly activated aryl halides under high pressure conditions. 9 Hurtwig and Buchwald reported the amidation of both activated and inactivated aryl halides with amines, using Pd or i as a catalysts under mild reaction conditions. Room temperature ionic liquids (RTIL s) offer significant properties such as negligible vapor pressure, high thermal stability, lack of inflammability, solubility for organic, inorganic and organometallic compounds and non coordinating but good solvating ability. Apart from these features each ionic liquid shows unique chemical and physical properties by proper modification of its cation and anion. 10 ne of the first reports of aromatic amination using [bmim] P6 ionic liquids has been published by J. S. Yadav et al., 11 Scheme-5.2.

5 194 Reactions of different aromatic halides with amines in [bmim] P6 were found to complete in 6-8 hours with reasonably good yields. R R' X H Y [bmim] [P 6 ] R R' r.t. Y R= CEt, 2, C, Dimethyl phenoxy R'=, 2, appthoxy, Scheme: 5.2 -Arylation of amines in [bmim] [P6] ionic liquid. Tom Welton et al. 12 reported a nucleophilic aromatic substitution reaction of an activated aniline with an activated aryl halide in various ionic liquids, Scheme-5.3. However, the reaction times were longer and the yields were reported based on HPLC data. Scheme: 5.3 ucleophilic aromatic substitution reaction of an activated aniline with an activated aryl halide.

6 195 It is noted from the literature that aromatic nucleophilic substitution reactions generally take longer reaction times and the yields reported were not satisfactory. Here in, we aim to study aromatic nucleophilic substitution reactions with a better ionic liquid to reduce the reaction time, and also to check the recovery and reusability of the same.

7 Results and Discussion Different substituted nitrobenzene derivatives 12a-12f were chosen to study the aromatic nucleophilic substitution reactions with morpholine. The readily available ionic liquid A (trihexyl (tetradecyl) phosphonium tris (pentafluoroethyl) trifluoro phosphate) and the pyrrolidine based ionic liquid C, Chart-5.2, were chosen as reaction media. The treatment of 3,4-difluoronitrobenzene, 12a with morpholine in ionic liquid A resulted in the product 13a in 5 minutes with high yield. The product was isolated by direct filtration followed by washing with hexane. The generality of the above transformation could be demonstrated with other substituted nitro benzenes 12b-12f with morpholine in the same ionic liquid, table-5.1. The reactions were completed in less than 2 hours in most of the cases except for 12d, table-5.2. The reason for longer reaction time with 12d could be attributed to sluggish reactivity with morpholine. All the products 13a-13f were characterized using spectroscopic data. H 3 C H 3 C P A CH 3 P CH 3 C + I - Chart-5.2: Ionic liquid structures.

8 197 Table: 5.1 Aromatic nucleophilic substitution reactions of various substituted aryl halides using ionic liquid (A). Entry Aryl halides Product 1. 12a 2 13a b 12c b 13c Cl 12d 2 13d e 2 13e f 13f 2 The transformation of 3,4-difluoronitrobenzene 12a to 13a is particularly interesting as the same intermediate is used in the study of linezolid, Scheme-5.5. The same transformation is further studied

9 198 with ionic liquid C as it is more easily available. It is observed that the product 13a could be obtained in ionic liquid with high yield. The product could be isolated from the reaction mass by extraction with ethyl acetate followed by layer separation and concentration of the organic layer. The separated ionic liquid could be reused for the same reaction for four cycles, Scheme a 2 IL (C) morpholine r.t. 13a 2 Yield % Remarks irst cycle 90 Rxn completed Second cycle 86 " Third cycle 84 " ourth cycle 87 " Scheme: 5.4 Recovery and reusability of the pyrrolidine based ionic liquid (C). Similarly, a variety of aryl halides (12a-f) reacted smoothly with morpholine using ionic liquid as a medium to give the corresponding aryl amines (13a-f) in excellent yields in shorter reaction time, table- 5.2.

10 199 Table: 5.2 Comparison of yield and reaction time of aromatic nucleophilic substitution reactions in traditional organic solvent vs ionic liquid. SL. o. Product (13a-f) Reaction Time In IPA Yield (%) In ionic liquid (A) Reaction Yield Time (%) 1 13a 12 hrs 80 5 min b 6.0 hrs min c 6.0 hrs hr d 12 hr* hrs e 12 hrs* hrs f 12 hrs hrs 79 * Reaction not completed even after 12 hours. It is interesting to note that the recovery and reusability of ionic liquids for four successive cycles resulted in high yields. The nitro functionality of the product 13a, is reduced with Raney i in methanol to give the corresponding amino compound 14. The conversion of the amine to linezolid 2 is well established in the literature, 13 Scheme-5.5.

11 a Morpholine IL, rt 2 13a MeH Raney i rt, 20 psi H 2 14 Cbz-Cl/aHC 3 Actetone/water Linezolid 2 16 H (R)-Glycidyl butyrate n-buli/th - 40 to -45 o C Cbz H 15 Scheme: 5.5 Synthetic scheme of linezolid.

12 Conclusion In conclusion, we have demonstrated the aromatic nucleophilic substitution in ionic liquids. The methodology was found to be more superior compared to the conventional method due to shorter reaction time, ease of operation, complete conversion of the reaction and reusability of the ionic liquid. Conclusively, the novel route described above is unique from other reported routes with respect to its core synthetic strategy. We observed that aromatic nucleophilic reactions in ionic liquids proceeded faster with higher yields, whereas in normal classical solvents for e.g., iso-propyl alcohol, the reaction rate were very slow with lower yields. Recovery and reusability of ionic liquids has been studied and demonstrated without compromising on yields. In order to demonstrate the significance of aromatic nucleophilic substitution reactions in ionic liquids, we demonstrated a short and practical enantioselective synthesis of linezolid 2.

13 Experimental Section All the chemicals and reagents used were of LR grade. 1 H MR spectra were obtained on a Varian Gemini 2000 model 400 MHz instrument (Chemical shifts in ppm) with TMS as internal standard and mass spectrum was run on HP5989 spectrometer. General experimental procedure: To a stirred solution of nitro compound (1.0 eq) in isopropyl alcohol (30 vol) or ionic liquid (3.0 vol), morpholine (3.0 eq) was added, and the reaction mixture was left to stir at room temperature. The progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, the yellow solid obtained was filtered and washed with water followed by n-hexane (twice). The product was dried in the oven at C for 6 hours (examples 13a-e). Preparation of 4-(2-fluoro-4-nitrophenyl) morpholine (13a): To a stirred solution of 3,4-difluoro nitrobenzene 12a ( mmol) in ionic liquid A (3.0 vol), morpholine ( mmol) was added, and the reaction mixture was left to stir at room temperature. The progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, obtained yellow solid was filtered and washed with water followed by n-hexane (twice), after which the product was dried in the oven at C for 6 hours to afford the 13a in 90% yield. 1 H MR (400 MHz, CDCl3): δ (dd, J=2.4, 9.2 Hz, 1H), (dd, J=2.8, 12.8 Hz, 1H), (t, J=8.8 Hz, 1H),

14 (t, J=4.8 Hz, 1H), (t, J=4.8 Hz, 4H) ppm; Mass: m/z 227 (M+1). Preparation of 4-(3,5-difluoro-4-nitrophenyl) morpholine (13b): The corresponding nitro compound was treated with morpholine in ionic liquid A by following the general procedure to afford the 13b in 70% yield. 1 H MR (400 MHz, CDCl3): δ (m, 1H), (m, 1H), (t, J=4.4 Hz, 4H), (t, J=4.4 Hz, 4H) ppm; Mass: m/z 245 (M+1). Preparation of 4-(2,6-difluoro-4-nitrophenyl) morpholine (13c): The corresponding nitro compound was treated with morpholine in ionic liquid A by following the general procedure to afford the 13c in 74% yield. 1 H MR (400 MHz, CDCl3): δ (dd, J=1.2, 2.8 Hz, 1H), (dd, J=1.2, 2.4 Hz, 1H), (t, J=4.8 Hz, 4H), (t, J=3.2 Hz, 4H) ppm; Mass: m/z 245 (M+1). Preparation of 4-(4-nitrophenyl) morpholine (13d): The corresponding nitro compound was treated with morpholine in ionic liquid A by following the general procedure to afford the 13d in 68% yield. 1 H MR (400 MHz, CDCl3): δ (m, 2H), (m, 2H), (t, J=4.8 Hz, 4H), (t, J=4.8 Hz, 4H) ppm; Mass: m/z 209 (M+1). Preparation of 4-(4-nitrophenyl) morpholine (13e): The corresponding nitro compound was treated with morpholine in ionic liquid A by following the general procedure to afford the 13e in 88% yield. 1 H MR (400 MHz, CDCl3): δ (m, 2H), (m, 2H),

15 (t, J=4.8 Hz, 4H), (t, J=4.8 Hz, 4H) ppm; Mass: m/z 209 (M+1). Preparation of 4-(2,4-dinitrophenyl) morpholine (13f): To a stirred solution of nitro compound 12f (9.874 mmol) in ionic liquid A (3.0 vol), morpholine ( mmol) was added, and the reaction mixture was left to stir at room temperature. The progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, DM water was added to the reaction mixture, and stirred for minutes, after which the unreacted starting material was precipitated as a solid. The solid was filtered, the filtrate was extracted with ethyl acetate, and the organic part was washed with water and brine solution. The solvent was concentrated under reduced pressure, and high vacuum was applied to give a yellow solid as a desired product 13f in 79% yield. 1 H MR (400 MHz, CDCl3): δ (d, J=2.4 Hz, 1H), (dd, J=2.4, 9.4 Hz, 1H), (d, J=9.6 Hz, 1H), (t, J=4.4 Hz, 4H), (t, J=4.4 Hz, 4H) ppm; Mass: m/z 254 (M+1). 3-fluoro 4-morpholinyl aniline (14): A solution of 3-flouro 4- morpholinyl nitrobenzene (13a) 10g (44 mmol) in methanol was hydrogenated over Raney nickel (0.5 ml) on Parr hydrogenation instrument for 8 h at psi pressure at room temperature. The catalyst was separated, and the solvent was evaporated to a minimum amount on a rotavapor. Petroleum ether was added, and stirred for 15 min. The precipitated yellow solid was filtered and dried in oven at 75 0 C for 4 hours to give the corresponding amine compound 14 in

16 205 quantitative yield with 98.6% purity by HPLC. 1 H MR (CDCl3, 200 MHz): δ (m, 1H), (m, 2H), (m, 4H), (br s, 2H), (m, 4H); MS: m/z 196 (M + ). (5S)- 3-(3-fluoro 4-morpholinophenyl)- 5-Hydroxy methyl 1,3- oxazolan-2-one (16): To a stirred solution of 14 (3-(3-fluoro-4- morpholino -benzoyloxy carbonyl aniline)) 5.0 g (14.6 mmol) in anhydrous TH (75 ml) under nitrogen atmosphere, n-butyl lithium (8.7 ml of 15% sol. in hexane;136 mmol) was added at 40 0 C followed by (R)-glycidyl butyrate (1.2 eq.) and stirred for 2 hours at the same temperature. Then the reaction mixture was brought to room temperature and stirring was continued overnight at the same temperature. The reaction mass was then poured into ice cold water, and the compound was extracted into ethyl acetate. The organic solvent was evaporated under vacuum to give a thick syrup. The syrup was dissolved in minimum amount of toluene and stirred for 30 minutes. The precipitated white solid was filtered and dried in oven at 70 0 C for 3 hours to afford compound 16 in 95% yield with 99.49% chemical purity and 99.36% chiral purity by HPLC, m.p C. The spectral data were comparable with the reported data. 1 H MR (CDCl3, 200MHz): δ 7.44 (dd, J=2.1, 14.4 Hz, 1H), 7.1 (dd, J=2.4, 8.9 Hz, 1H), 6.97 (br s, 1H), 4.78 (m, 1H), 3.95 (m, 3H), 3.88 (t, J=4.7 Hz, 4H), 3.76 (d, J=13.1 Hz, 1H), 3.08 (t, J=4.2 Hz, 4H), 2.40 (br s, 1H); IR (KBr, cm-1): 3432, 3263, 2925, 1748, 1734, 1523, 1465, 1454, 1441, 1424, 1231, 1044, 872, 752; MS: m/z 296; MR: C and [α ] D = -54 (1%; CHCl3).

17 206 Linezolid (2): xazolidinone compound 16 was then converted into the corresponding azide in two steps with 92% overall yield. In first step oxazolidinone was treated with methanesulfonylchloride in dichloromethane solvent at 0 0 C using triethylamine as a base. After completion of the reaction, the organic layer was washed with water and distilled out under reduced pressure to afford the mesyl product in 95% yield, which was treated with sodium azide in dimethylformamide at 75 0 C. After completion of the reaction, the reaction mass was diluted with water and the product was extracted into ethyl acetate and distilled out the organic solvent to afford the azide product in 95% yield. inally, the azide function was reduced with H2 using Pd/C to furnish the crude amine, which was treated with acetic anhydride in the presence of pyridine converted to afford linezolid 2 in 92% yield with m.p C. 1 H MR (CDCl3, 200 MHz): δ (dd, J=2.2, 14.6 Hz, 1H), (dd, J=1.8, 9.1 Hz, 1H), (t, J=9.1 Hz, 1H), (t, J=6.0 Hz, 1H), (m, 1H), (t, J=8.9 Hz, 1H), (t, J=4.5 Hz, 4H), (dd, J=1.8, 7.0 Hz, 1H), (dd, J=3.2, 5.9 Hz, 1H), (dd, J=5.5, 8.5 Hz, 1H), (t, J=4.6 Hz, 4H), (s, 3H); IR (KBr, cm-1): 3339, 2818, 1742, 1663, 1516, 1424, 1228, 1198, 1116, 871, 754. MS: m/z 338. [α ] D = -54 (1%; CHCl3).

18 Spectral data 1 H MR spectrum (400MHz, CDCl3) of compound 13a: 2 13a Mass spectrum of compound 13a:

19 208 IR spectrum of compound 13a: 1 H MR spectrum (400MHz, CDCl3) of compound 13d: 2 13d

20 209 Mass spectrum of compound 13d: 1 H MR spectrum (400MHz, CDCl3) of compound 13e: 2 13e

21 210 Mass spectrum of compound 13e: 1 H MR spectrum (400MHz, CDCl3) of compound 13f: f

22 211 Mass spectrum of compound 13f: 1 H MR spectrum (400MHz, CDCl3) of compound 14: H 2 14

23 212 Mass spectrum of compound 14: 1 H MR spectrum (400MHz, CDCl3) of compound 16: H 16

24 213 Mass spectrum of compound 16: IR spectrum of compound 16:

25 214 1 H MR spectrum (400MHz, CDCl3) of compound 2: H CH H MR spectrum (400MHz, CDCl3) of compound 2:

26 215 IR spectrum of compound 2: Mass spectrum of compound 2: H CH 3 2

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