WO2022038631A1

WO2022038631A1 - Quaternary ammonium fluoride salts for fluorination reactions

Info

Publication number: WO2022038631A1
Application number: PCT/IN2021/050774
Authority: WO
Inventors: Syed Gulam DASTAGER; Jayant Maroti Gajbhiye; Madhukar Shyam SAID
Original assignee: Council of Scientific and Industrial Research CSIR
Current assignee: Council of Scientific and Industrial Research CSIR
Priority date: 2020-08-18
Filing date: 2021-08-11
Publication date: 2022-02-24
Anticipated expiration: 2023-02-18

Abstract

The present invention relates to a quaternary ammonium fluoride salt selected from formula (Ia) and formula (Ib), process for the preparation thereof and their use in the SN2 and SNAr fluorination reaction of sulfonates and halides.(1a), (1b) (^tΒuΟΗ)Μe₃ΝF (di- ^tBuOH)₂Me₂NF (Ia)-C₇H₁₈NOF (Ib)-C₁₀H₂₄NOF

Description

QUATERNARY AMMONIUM FUUORIDE SAETS FOR FLUORINATION REACTIONS

FIELD OF THE INVENTION

The present invention relates to a quaternary ammonium fluoride salt selected from formula (la) and formula (lb), a process for the preparation and application thereof. More particularly, the present invention relates to a quaternary ammonium fluoride salt selected from formula (la) and formula (lb), process for the preparation thereof and their use in the SN2 and SNAr fluorination reaction of sulfonates and halides.

BACKGROUND AND PRIOR ART OF THE INVENTION

More than 30-40% drugs in the market contain at least one fluorine atom. The small size and high electronegative features of the fluorine atom are the key factors to form a hydrogen bonding with different sites of enzymes to control bio-selectivity, stability, lipophilicity and pKa value of the drug molecules. Due to the short half-life time of 18F, isotope of fluorine is extensively used in radiopharmaceutical and nuclear medicine for the applications in positron emission tomography (PET).

For the incorporation of fluorine into aliphatic and aromatic fragments, several fluorinating reagents have been developed. For the deoxyfluorination of aliphatics, diethylamino sulfur trifluoride and Difluoro(morpholino)sulfonium tetrafluoroborate are used, but these reagents are expensive, hazardous, and possess no selectivity. Similarly, in aromatic SNAT deoxyfluorination Bis(2-methoxyethyl)aminosulfur Trifluoride (Deoxofluor), 4-tert-Butyl- 2,6-dimethylphenylsulfur trifluoride (Fluolead), N,N-Diethyl-S,S-difluorosulfiliminium tetrafluoroborate (Xtalfluor), 2-Pyridinesulfonyl Fluoride (PyFluor), are employed, but these reagents have a high cost and provided limited substrate scope. The anhydrous alkali metal fluorides (MF) are used as a common fluoride source in fluorination, but these salts have low solubility in organic solvents, require a very high temperature and long endurance for completion of the reaction. Due to the harsh conditions, many functional groups are not sustained and lead to undesired side product formation. To overcome this issue, a source of hydrogen is usually added. Some of the fluorinating agents are as follows

Diethylaminosulfur Tetrabutylammonium tetramethylammonium

Triflouride fluoride fluoride

(J. H. Clark, Chem. Rev. 1980, 80, 429-452, M. Namikoshi, B. Kundu, and K. L. Rinehart, J. Org. Chem., 1991, 56, 5464-5466, R. K. Sharma, and J. L. Fry, J. Org. Chem. 1983, 45, 2112-2114).

The above-mentioned fluorinating agents may be used, but they are highly hygroscopic. Due to the low thermal stability and hygroscopicity, there is a need to synthesize a new quaternary ammonium fluoride salt, which contains internal hydrogen bonding for stabilization of fluorine.

Article titled “Tetrabutylammonium Tetra(tert-Butyl Alcohol)-Coordinated Fluoride as a Facile Fluoride Source” by Dong Wook Kim et al. published in Angew. Chem. 2008, 120, 8532 -8534 reports tetrabutylammonium tctra(/ rt-butyl alcohol) coordinated fluoride, TBAF(/BLIOH)4 as a promising new fluoride source.

Very few reports are present in literature for synthesizing the bench stable fluorine complexes. Recently few scientists have synthesized stable, less hygroscopic fluorine complexes from fluoride -tert-butyl alcohol complex.

Thus, it may be observed that the known fluorinating reagents are highly hygroscopic, have low thermal stability and are expensive, so, there is a need to synthesize a new quaternary ammonium fluoride salt, which contains internal hydrogen bonding for stabilization of fluorine.

OBJECTIVES OF THE INVENTION

Main objective of the present invention is to provide a stable quaternary ammonium fluoride salt selected from formula (la) and formula (lb).

Second objective of the present invention is to provide a process for the preparation of the quaternary ammonium fluoride salts of formula (la) and formula (lb). Third objective of the present invention is to provide, SN2 and SNAT fluorination reaction of sulfonates and halides by using the quaternary ammonium fluoride salts of formula (la) and formula (lb).

ABBREVIATIONS

TBAF : Tetrabutylammonium fluoride

TMAF : Tetramethylammonium fluoride

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a quaternary ammonium fluoride salt selected from formula (la) and formula (lb)

(Ia)-C₇Hi8NOF (Ib)-CioH24NOF

The present invention also provides a process for the preparation of the quaternary ammonium fluoride salt selected from formula (la) and formula (lb) comprising the steps of: a) stirring a mixture of isobutylene oxide, and a respective amine at a temperature in the range of 25 to 50°C for a time period in the range of 70-80 hours to afford a viscous liquid reaction mixture; b) dissolving the reaction mixture of step (a) then adding an alkyl halide and heating at a temperature in the range of 50 to 100°C for 2 to 6 hours to afford a compound containing crystalline solid; c) passing the compounds of step (b) through ion exchange resin in a fluorine source from a solvent followed by removing the solvent to afford the quaternary ammonium fluoride salt selected from formula (la) and formula (lb).

The present invention also provides a process for the fluorination of aliphatic or aromatic compounds comprising stirring the reaction mixture of aliphatic or aromatic compound, halide precursor, formula (la) or formula (lb) compound in a solvent at a temperature in the range of 60 to 100°C for a time period in the range of 1 to 24 hours to afford fluorinated product.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig 1 : Demonstration of hygroscopicity at 27 °C in 15 min and 2h under humidity of 76%.

It was observed that after 15 min TBAF is capturing moisture and becomes a liquid but the compounds (la) and (lb) are stable. After 2-4h, (lb) also captures moisture, indicating that (la) is more stable than lb and TBAF.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

The present invention provides a quaternary ammonium fluoride salt selected from formula (la) and formula (lb)

(Ia)-C₇Hi₈NOF (Ib)-CioH₂4NOF la is 2-hydroxy-N,N,N,2-tetramethylpropan-l- ammonium fluoride lb is 2-hydroxy-N-(2-hydroxy-2-methylpropyl)-N,N,2-trimethylpropan-l- ammonium fluoride

The quaternary ammonium fluoride salt selected from formula (la) and formula (lb) are stable and non-hygroscopic. Figure 1 depicts the demonstration of hygroscopicity at 27 °C in 15 min under humidity of 76% for la and lb when compared with TBAF. It was observed that after 15 min TBAF is capturing moisture and becomes a liquid but (la) and (lb) are stable. After 2h, lb also captures moisture, indicating that (la) is more stable than lb and TBAF.

The present invention provides a process for the preparation of quaternary ammonium fluoride salt selected from formula (la) and formula (lb) comprising the steps of: a) stirring a mixture of isobutylene oxide, and a respective amine at a temperature in the range of 25 to 50°C for a time period in the range of 70-80 hours to afford a viscous liquid reaction mixture; b) dissolving the reaction mixture of step (a) then adding an alkyl halide and heating at a temperature in the range of 50 to 100°C for 2 to 6 hours to afford a compound containing crystalline solid; c) passing the compound of step (b) through ion exchange resin in a fluorine source from a solvent followed by removing the solvent to afford the quaternary ammonium fluoride salt selected from formula (la) and formula (lb).

The solvent of step (c) is selected from tetrahydrofuran or water.

The alkyl halide is alkyl iodide, alkyl bromide, and alkyl chloride. In one of the features the alkyl halide in step (b) is methyl iodide.

The ion exchange resin is anion exchange resin, and flourine source is KF, HF, and NaF.

The amine is selected from -methyl amine and dimethyl amine. Methyl amine is used to obtain compound of formula (la) and dimethyl amine is used to obtain compound of formula (lb).

The process for the preparation of the quaternary ammonium fluoride salts selected from formula (la) and formula (lb) is shown in scheme 1 :

Scheme 1: a) amine, Isobutylene oxide, 50 °C, 3 days; b) MeY (1.5mmol), THF 60 °C, 2 h; c) KF, Amberlite® IRA400 ion exchange resin, (Y=I, Cl, Br,)

The present invention provides a process for the fluorination of formula (II) comprising stirring the reaction mixture of reactant compound of formula (II), quaternary ammonium fluoride salts selected from formula (la) or formula (lb) compound in a solvent at a temperature in the range of 60 to 100°C for a time period in the range of 1 to 24 hours to afford fluorinated product (III), wherein the selectivity to the product is at least 30-93%.

The process for the fluorination of compounds of formula (II) is shown in scheme 2 below:

Comp, la or lb R^F

Solvent, 60 °C-100°C R!

1 to 24 h Ill

X = Leaving Group

Scheme 2

Wherein, R or Ri may be same or different, linear or branched and are selected from the group consisting of hydrogen, alkyl, aryl, alkyl aryl, haloalkyl, hydroxy alkyl, alkoxy, hydroxy, halo, cyano, heteroaryl, heteroalkyl, alkyl heteroaryl, substituted or unsubstituted aryl/alkyl, alkenyl, alkenyl aryl, alkenyl heteroaryl, alkynyl, alkynyl aryl, alkynyl heteroaryl, cycloalkyl, heterocycloalkyl, alkyl cycloalkyl, alkyl heterocycloalkyl, alkyl carboxy, acyl, alkyl acyl, alkyl acyloxy, alkyl alkoxy, alkyl carbonyl, aryl carbonyl, alkoxycarbonyl, alkyl alkoxycarbonyl, aminocarbonyl, alkyl aminocarbonyl, alkyl acylamino, alkyl ureido, amino, alkyl amino, sulfonyloxy, alkyl sulfonyloxy, sulfonyl, alkyl sulfonyl, sulfinyl, alkyl sulfinyl, alkyl sulfanyl and alkyl sulfonylamino;

R and Ri together may form a cyclic ring which may optionally be substituted; ring may optionally contain heteroatom;

X is selected from OMs, OTs, OTf, ONs, Cl, Br or I.

The solvent is selected from acetonitrile, dimethylformamide and tert-butyl alcohol.

The compound of formula (II) is selected from Phenol, Heterocycle, terpene and sugar.

The fluorinated product of formula (III) is selected from -(3-Fluoropropoxy)-l,l'-biphenyl (7a), Alnustin fhioride(8a), Mosloflavone fluoride (9a), Estronfluoride (10a), 8- (Fluoromethyl)hexadecane(I Ia), 9-(Fluoromethyl)heptadecane (12a), (3-

Fluoropropoxy)benzene (13a), l-(3-Fluoropropoxy)-2,3-dimethylbenzene (14a), 2-(3- Fluoropropoxy)naphthalene (15a), l-(3-Fluoropropoxy)-4-methoxybenzene (16a), (3- Fluoropropyl)benzene (17a), 4-(3-Fluoropropoxy)-l,l'-biphenyl (18a), 4-Bromo-2-chloro-I- (3-fluoropropoxy)benzene (19a), l-(3-Fluoropropoxy)-lH-benzo[d][l,2,3]triazole (20a), 2- Benzyl-4-chloro-I-(3-fluoropropoxy)benzene (21a), 4-(3 -Fluoropropoxy )benzonitrile (22a), 9-(2-Fluoroethyl)-9H-carbazole (23a), I-(3-Fluoropropoxy)-2,3-dimethoxylbenzene(24a) 3- Fluorostigmasterol (25a), Cholesteryl fluoride (26a), N4’ -3 -Fluoropropylciprofloxacin methyl ester(27a), 5-(Fluoromethyl)-2, 2-dimethyltetrahydrofuro [2, 3-d][l, 3] dioxol-6-ol (28a), 5-((Benzyloxy)methyl)-6-fluoro-2,2-dimethyltetrahydrofuro[2,3-d][l,3]dioxole

(29a),4-(2,2-Dimethyl-l,3-dioxolan-4-yl)-6-fluoro-2,2-dimethyltetrahydrofuro[3,4- d][l,3]dioxole (30a), l-(4-chlorophenyl)-2-fluoroethan-l-one(31a), 2-Fluoro-l-(naphthalen-

2-yl)ethan-l-one (32a), l-([l,l'-Biphenyl]-4-yl)-2-fluoroethan-l-one (33a), 2-fluoro-l-(4- methoxyphenyl)ethan-l-one (34a), 2-Fluoro-l-(3-methoxyphenyl)ethan-l-one (35a), 1- fluoro-4-nitrobenzene (36), ethyl 2-fluorobenzoate(37), l-(2-fluorophenyl)ethan-l-one(38), 2-fluorobenzonitrile (39), l-(3-fluorophenyl)ethan-l-one(40), 3-fluoro-l,l'-biphenyl (41), ethyl 4-fluorobenzoate(42), l,4-difluorobenzene(43), (4- fluorophenyl)(phenyl)methanone(44), 2-fluoronaphthalene (45), 2-fluoropyridine(46), l-(4'- fluoro-[ 1 , 1 '-biphenyl] -3-yl)ethan- l-one(47), 5-Fluoro-N-(4-methoxyphenyl)pentanamide

(49), l-(2-Fluoroethyl)-4-methoxybenzene (52).

The fluorinated products of formula (III) are shown below:

A comparative study for the selectivity of a products of a process of selective fluorination of aliphatic or aromatic compounds using quaternary ammonium salts of formula la or formula lb, Tetrabutylammonium fluoride trihydrate (TBAF(H2O)3 and Tetramethylammonium fluoride(TMAF) at the temperature in the range of 60 to 100°C for a time period in the range of 1 to 4 hours in a solvent shown in scheme 3.

Selctive SN2 Fluorination

Scheme 3 From the scheme 3A and 3B, it is observed that the yield of the fluorinated product is in the range of 59% to 84% by using the compound of la or lb which is more as compared to the reported fluorinating agents of Tetrabutylammonium fluoride trihydrate (TBAF(H2O)3 and Tetramethylammonium fluoride (TMAF).

The process for the selective desilylation of aromatic silane group using quaternary ammonium salts of formula la or lb comprises reacting aromatic silane compound with quaternary ammonium salts of formula la or lb and Tetrabutylammonium fluoride trihydrate (TBAF(H2O)3 and Tetramethylammonium fluoride(TMAF) at the temperature in the range of 25 to 30°C for a time period in the range of 1 to 4 hours in a solvent to afford desilylation products (Scheme 3 C). From the scheme 3 C it is observed that the yield of the desilylation product is more by using the compound of la or lb than by using of Tetrabutylammonium fluoride trihydrate TBAF(H2O)3 and Tetramethylammonium fluoride(TMAF). EXAMPLES

Following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.

Example 1: Synthesis of quaternary ammonium fluoride salt

Step-1: stirring a mixture of isobutylene oxide, and a respective amine at a temperature in the range of 25 to 50°C for a time period in the range of 70-80 hours to afford a viscous liquid reaction mixture.

Step-2: In the sealed tube viscous liquid obtained from step-1 was dissolved in THF then methyl iodide (3mmol) was added and heated at 50 °C to 100 °C for 2h to 6h. The compounds were concentrated at reduced pressure to give yellow solid 3 and 4.

Step-3: The yellow solid obtained from step-2 then pass through Amberlite® IRA400 ion exchange resin in fluoride sources from H2O as a solvent. Water was removed at 40 °C to gave quaternary ammonium fluoride salt (la and lb)

2-hydroxy-N,N,N,2-tetramethylpropan-l- ammonium iodide (3):

'H NMR (400MHz, MeOD-d₄) 5 4.75 (br s, 11 H), 2.82 (s, 6 H) ¹³C NMR

(101MHz, MeOD-d₄) 74.9, 71.0, 56.4, 31.0

2-hydroxy-N-(2-hydroxy-2-methylpropyl)-N,N,2-trimethylpropan-l- ammonium iodide

5.20 (s, 4 H), 4.99 (s, 6 H), 3.00 (s, 9

H) ¹³C NMR (101MHz, MeOD-d₄) 75.0, 71.2, 55.5, 5, 31.3

2-hydroxy-N,N,N,2-tetramethylpropan-l- ammonium fluoride (la)

'H NMR (400MHz, CHsCN-ds) 5 3.62 (br. s., 4 H), 3.29 (s, 6 H), 1.33 (s, 9 H) ¹³C NMR (101MHz, CHsCN-ds) 5, 73.3, 70.2, 55.7, 31.2, 2.0, ¹⁹F NMR (376 MHz, CDC) 5 156.12;

2-hydroxy-N-(2-hydroxy-2-methylpropyl)-N,N,2-trimethylpropan-l- ammonium fluoride (lb):

'H NMR (400MHz, CHsCN-ds) 5 3.62 (br. s., 4 H), 3.29 (s, 6 H), 1.33 (s, 9 H) ¹³C NMR (100|MHz, CHsCN-ds) 5 73.3, 70.2, 55.7, 31.2, 2.0, ¹⁹F NMR (376 MHz, CDCh) 5 158.12;

Example 2: general procedure for fluorination:

In a flame dried reaction vials or round bottom flask sulfonate or halide precursor of formula II (Immol) and quaternary ammonium fluoride salt of formula (la) or formula (lb) was added in a CHsCN/DMF and stirred at 60 °C to 100 °C for 1 h to 24 h. After completion of reaction mixture was concentrated under reduced pressure. The crude product was purified by flash column chromatography using EtOAc/hexane to obtain fluorinated products from formula III.

(3-Fluoropropoxy)-l,r-biphenyl (7a): 'H NMR (400 MHz, CDCh) 5 7.66 - 7.53 (m, 4 H), 7.44 (t, J = 7.6 Hz, 2 H), 7.32 (d, J = 7.3 Hz, 1 H), 6.98 (d, J = 8.9 Hz, 2 H), 4.74 (t, J= 5.8 Hz, 1 H), 4.62 (t, J = 5.8 Hz, 1 H), 4.15 (t, J = 6.1 Hz, 2 H), 2.29 - 2.11 (m, 2 H); ¹³C NMR (100 MHz CDCh) 5 158.3, 140.8, 134.0, 128.7, 128.2, 126.7, 126.7, 114.8, 81.5 (d, J = 164.15 Hz), 63.8 (d, J = 4.62 Hz), 30.6 (d, J = 20.05 Hz); ¹⁹F NMR (376 MHz, CDCh) 5 222.16;

Alnustin fluoride (8a) : 'H NMR (400 MHz, CDCh) 5 7.89 (d, J = 4.3 Hz, 2 H), 7.53 (m, 3 H), 6.84 (s, 1 H), 6.66 (s, 1 H), 4.86 (t, J= 6.1 Hz, 1 H), 4.76 (t, J= 6.1 Hz, 1 H), 4.23 (t, J = 5.8 Hz, 2 H), 4.00 (s, 3 H), 3.91 (s, 3 H), 2.35 - 2.20 (m, 2 H); ¹³C NMR (100 MHz CDCh) 5

177.2, 161.2, 157.9, 154.7, 151.4, 140.5, 131.6, 131.3, 129.0, 126.0, 113.0, 108.4, 108.4,

82.2, (d, J= 163. 83 Hz), 76.8(d, J= 5. 39 Hz), 61.5, 56.3, 31.4 (d, J = 20.40 Hz); ¹⁹F NMR (376 MHz, CDCh) 5 218.01

Mosloflavone fluoride (9a) : , 'H NMR (400 MHz, CDCh) 5 8.10 - 8.05 (m, 2 H), 7.53 - 7.49 (m, 3 H), 4.88 (t, J = 5.8 Hz, 1 H), 4.75 (t, J = 6.1 Hz, 1 H), 4.26 (t, J = 6.1 Hz, 2 H), 3.97 (s, 3 H), 3.91 (s, 3 H), 3.85 (s, 3 H), 2.36 - 2.26 (m, 2 H); ¹³C NMR (100 MHz CDCh) 5 173.8, 157.8, 153.4, 151.3, 141.4, 140.2, 130.8, 130.5, 128.5, 128.2, 113.2, 96.1, 81.4 (d, J = 163. 38 Hz) 71.0(d, J = 5. 39 Hz), 61.5, 60.1, 56.3, 31.3, (d, J = 20. 04Hz); ¹⁹F NMR (376 MHz, CDCh) 5 218. 02.

Estronfluoride (10a): NMR (400 MHz, CDCh) 5 7.22 (d, J= 8.2 Hz, 1 H), 6.73 (dd, J= 2.1, 8.7 Hz, 1 H), 6.67 (d, J = 2.7 Hz, 1 H), 4.71 (t, J = 5.7 Hz, 1 H), 4.59 (t, J = 6.0 Hz, 1 H), 4.08 (t, J= 6.0 Hz, 2 H), 2.92 - 2.88 (m, 2 H), 2.56 - 2.48 (m, 1 H), 2.37 (dd, J= 8.7, 19.23, Hz, 1 H), 2.28 - 2.16 (m, 3 H), 2.12, (d, J= 2.7 Hz, 1 H), 2.03 (br. s., 2 H), 1.98 (s, 1 H), 1.65 - 1.61 (m, 3 H), 1.59 - 1.54 (m, 3 H), 0.92 (s, 3 H); ¹³C NMR (100 MHz , CDCh) 5 221.0, 156.7, 137.8, 132.2, 126.4, 115.5, 112.1, 81.6 (d, J= 163.90 Hz), 63.4 (d, J = 4.79 Hz), 50.4, 48.0, 45.0, 38.3, 35.9, 31.5, 30.6, 29.7 (d, J= 5.75 Hz), 26.5, 25.9, 21.6, 13.8 ; ¹⁹F NMR (376 MHz, CDCh) 5 222.25.

8-(Fluoromethyl)hexadecane (Ila) : 'H NMR (400 MHz CDCh) > 4.41 (d, J = 4.9 Hz, 1 H), 4.28 (d, J = 5.5 Hz, 1 H), 1.67 - 1.56 (m, 2 H), 1.29 (m, 25 H), 0.89 (t, J = 6.7 Hz, 6 H); ¹³C NMR (100 MHz CDCh) 5 86.6(d, J = 168.00 Hz), 39.0 (d, J = 17.09 Hz), 31.9, 31.8 30.6, (d, J = 5.79 Hz), 29.9, 29.6, 29.6, 29.6, 29.3, 29.3, 26.8, 22.8, 14.1; ¹⁹F NMR (376 MHz, CDCh) 5 221. 01.

9-(Fluoromethyl)heptadecane (12a) : 'H NMR (400 MHz, CDCh) 5 4.40 (d, J = 5.5 Hz, 1 H), 4.29 (d, J = 5.5 Hz, 1 H), 1.77 - 1.48 (m, 2 H), 1.28 (m, 27 H), 0.89 (t, J = 6.4 Hz, 6 H); ¹³C NMR (100 MHz CDCh) 5 88.5 (d, J= 167.23 Hz), 39.0 (d, J= 17.30 Hz), 31.9 31.8 30.6 (d, J= 5.7 Hz), 30.0, 29.6, 29.6, 29.3, 26.8, 26.8, 22.7, 14.1; ¹⁹F NMR (376 MHz, CDCh) 5 221. 01.

(3-Fluoropropoxy)benzene (13a) : 'H NMR (400 MHz, CDCh) 5 7.49-7.25 (m, 5H), 4.57 (t, J= 5.8 Hz, 1H), 4.46 (t, J= 6.1 Hz, 1H), 2.82 (t, J= 7.6 Hz, 2H), 2.17-1.99 (m, 2H); ¹³C NMR (100 MHz, CDCh) 5 141.1, 128.4, 128.5, 126.0, 83.6 (d, J= 164.15 Hz), 32.5 (d, J = 20.04 Hz), 31.3, (d, J= 5.39 Hz); ¹⁹F NMR (376 MHz, CDCh) 5223.19. l-(3-Fluoropropoxy)-2,3-dimethylbenzene (14a): ³H NMR (400 MHz, CDCh) 5 7.09 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 7.3 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 4.78 (t, J = 5.5 Hz, 1H), 4.65 (t, J = 5.5 Hz, 1H), 4.13 (t, J = 5.8 Hz, 2H), 2.32 (s, 3H), 2.30-2.21 (m, 2H), 2.20 (s, 3H); ¹³C NMR (100 MHz, CDCh) 5 156.6, 138.0, 126.9, 125.2, 122.4, 108.9, 81.00 (d, J = 164.92 Hz), 63.8 (d, J = 5.39 Hz), 30.7 (d, J = 20.04 Hz), 20.1, 11.6; ¹⁹F NMR (376 MHz, CDCh) 5223.18.

2-(3-Fluoropropoxy)naphthalene (15a): ³H NMR (400 MHz, CDCh) 5 7.85-7.74 (m, 3H), 7.47 (ddd, J= 1.4, 6.9, 8.2 Hz, 1H), 7.37 (ddd, J= 1.4, 6.9, 8.2 Hz, 1H), 7.21-7.16 (m, 2H), 4.78 (t, J= 5.7 Hz, 1H), 4.66 (t, J= 5.7 Hz, 1H), 4.26 (t, J= 6.2 Hz, 2H), 2.32-2.17 (m, 2H); ¹³C NMR (100 MHz, CDCh) 5 156.7, 134.6, 129.4, 129.0, 127.6, 126.7, 126.4, 123.6, 118.8, 106.6, 81.6, 81.0, 63.5, 30.5, 30.3; ¹⁹F NMR (376 MHz, CDCh) 5222.48. l-(3-Fluoropropoxy)-4-methoxybenzene (16a) ³H NMR (400 MHz, CDCh) 5 6.87(s, 4 H), 4.72 (t, J= 5.8 Hz, 1 H), 4.60 (t, J= 5.8 Hz, 1 H), 4.07 (t, J= 6.1 Hz, 2 H), 3.78 (s, 3 H), 2.23 - 2.09 (m, 2 H); ¹³C NMR (100 MHz CDCh) 5 154.9, 152.9, 115.4, 114.6, 81.3, (d, J= 164. 16 Hz), 64.3 (d, J= 5.3 Hz), 55.7, 30.6 (d, J= 19.27 Hz); ¹⁹F NMR (376 MHz, CDCh) 5219. 01.

(3-Fluoropropyl)benzene (17a) : 'H NMR (400 MHz, CDCh) 5 7.42 - 7.32 (m, 2 H), 7.25 (br. s., 3 H), 4.57 (t, J= 5.8 Hz, 1 H), 4.47 (t, J = 6.1 Hz, 1 H), 2.81 (t, J= 7.6 Hz, 2 H), 2.14 - 1.98 (m, 2 H); ¹³C NMR (100 MHz CDCh) 5 141.2, 128.5, 128.4, 126.0, 83.9 d, J= 163.15 Hz), 32.1 (d, J = 20.04 Hz), 31.4 (d, J= 5.39Hz); ¹⁹F NMR (376 MHz, CDCh) 5217. 01. 4-(3-Fluoropropoxy)-l,l'-biphenyl (18a): 'H NMR (400 MHz, CDCh) 5 7.66-7.49 (m, 4H), 7.43 (t, J= 7.6 Hz, 2H), 7.32 (d, J= 7.3 Hz, 1H), 6.98 (d, J= 8.9 Hz, 2H), 4.74 (t, J = 5.8 Hz, 1H), 4.61 (t, J = 5.8 Hz, 1H), 4.16 (t, J= 6.1 Hz, 2H), 2.29-2.11 (m, 2H); ¹³C NMR (100 MHz CDCh) 5 158.2, 140.8, 134.0, 128.7, 128.2, 126.7, 126.7, 114.7, 81.5 (d, J = 164.15 Hz), 63.6 (d, J = 4.62 Hz), 30.5 (d, J = 20.05 Hz); ¹⁹F NMR (376 MHz, CDCh) 5 225.05.

4-Bromo-2-chloro-l-(3-fluoropropoxy)benzene (19a): ¹ H NMR (400 MHz, CDCh) 5 7.52 (d, J= 2.3 Hz, 1H), 7.33 (dd, J= 2.3, 8.7 Hz, 1H), 6.82 (d, J= 8.7 Hz, 1H), 4.76 (t, J= 5.7 Hz, 1H), 4.63 (t, J= 5.7 Hz, 1H), 4.14 (t, J= 6.0 Hz, 2H), 2.28-2.19 (m, 2H); ¹³C NMR (100 MHz, CDCh) 5 153.6, 132.7, 129.5, 124.1, 114.6, 112.8, 79.8 (d, J= 164.86 Hz), 65.9, (d, J = 4.79 Hz), 30.3, 30.2 (d, J= 20.13 Hz); ¹⁹F NMR (376 MHz, CDCh) 5 222.86.

1-(3-Fluoropropoxy)-lH-benzo[d][l,2,3]triazole (20a): ^JH NMR (400 MHz, CDCh) 5 7.52 (d, J= 2.3 Hz, 1H), 7.33 (dd, J= 2.3, 8.7 Hz, 1H), 6.83 (d, J= 8.7 Hz, 1H), 4.76 (t, J= 5.7 Hz, 1H), 4.65 (t, J = 5.7 Hz) 4.14 (t, J = 6.0 Hz, 2H), 2.27-2.17 (m, 2H); ¹³C NMR (100 MHz, CDCh) 5 153.6, 132.8, 130.5, 124.1, 114.6, 113.8, 80.4 (d, J= Hz, 164.85), 64.8, (d, J = 4.79 Hz), 30.2 (d, J= 20.13 Hz); ¹⁹F NMR (376 MHz, CDCh) 5223.85.

2-Benzyl-4-chloro-l-(3-fluoropropoxy)benzene (21a) ¹ H NMR (400 MHz, CDCh) 5 7.33- 7.27 (m, 2H), 7.26-7.13 (m, 4H), 7.09 (d, J= 2.7 Hz, 1H), 6.78 (d, J= 8.7 Hz, 1H), 4.58 (t, J = 5.7 Hz, 1H), 4.45 (t, J= 6.0 Hz, 1H), 4.06 (t, J= 6.0 Hz, 2H), 3.95 (s, 2H), 2.18-2.07 (m, 2H); ¹³C NMR (100 MHz, CDCh) 5 155.1, 140.1, 131.5, 130.3, 128.7, 128.4, 126.1, 126.1, 125.4, 112.3, 80.5 (d, J= 164.86 Hz), 63.8 (d, J= 4.79 Hz), 30.4 (d, J= 20.13Hz); ¹⁹F NMR (376 MHz, CDCh) 5223.19.

4-(3-Fluoropropoxy)benzonitrile (22a) H NMR (400 MHz, CDCh) 5 7.66 (d, J = 9.2 Hz, 2H), 7.00 (d, J = 8.5 Hz, 2H), 4.71 (t, J= 5.8 Hz, 1H), 4.61 (t, J = 5.5 Hz, 1H), 4.16 (t, J = 6.1 Hz, 2H), 2.29-2.13 (m, 2H); ¹³C NMR (100 MHz, CDCh) 5 162.0, 134.0, 119.2, 115.2, 104.2, 79.9 (d, J = 165.69 Hz), 63.8 (d, J = 4.62 Hz), 30.1(d, J = 2.04 Hz); ¹⁹F NMR (400 MHz, CDCh) 5222.65.

9-(2-Fluoroethyl)-9H-carbazole (23a): 'H NMR (400 MHz, CDCh) 5 8.17 (d, J = 7.9 Hz, 2H), 7.55-7.48 (m, 2H), 7.47-7.42 (m, 2H), 7.36-7.29 (m, 2H), 4.87 (t, J= 5.4 Hz, 1H), 4.75 (t, J= 4.88 Hz, 1H), 4.65 (t, J= 5.4 Hz, 1H), 4.63 (t, J= 4.8 Hz, 1H); ¹³C NMR (100 MHz, CDCh) 5 141.4, 125.8, 123.0, 120.4, 118.3, 108.5, 81.9 ( d, J = 172.6Hz), 44.2, (d, J = 22.3 Hz); ¹⁹F NMR (376 MHz, CDCh) 5 218.62. l-(3-fluoropropoxy)-3,5-dimethoxybenzene (24a): 'H NMR (500 MHz, CDCh) 5 6.10 (s, 3H), 4.71 (t, J= 5.8 Hz, 1H), 4.59 (t, J = 5.8 Hz, 1H), 4.07 (t, J = 6.1 Hz, 2H), 3.78 (s, 7H),

2.24 - 2.11 (m, 2H); ¹³C NMR (125 MHz, CDCh) 5 161.5, 160.6, 93.3, 93.1, 80.4 (d, J = 164.15 Hz), 63.5, 63.5 (d, J = 46.06 Hz), 55.3, 30.4 (d, J = 20.04 Hz); ¹⁹F NMR (376 MHz, CDCh)5 222.14;

3-Fluorostigmasterol (25a) : 'H NMR (400 MHz, CDCh) 5 5.35 (d, J= 5.0 Hz, 1 H), 5.19 - 5.14 (m, 1 H), 5.02 (dd, J = 8.6, 15.1 Hz, 1 H), 3.33 - 3.24 (m, 1 H), 2.35 - 2.19 (m, 2 H), 2.11 - 1.93 (m, 4 H), 1.88 - 1.80 (m, 2 H), 1.74 - 1.67 (m, 1 H), 1.58 (s, 3 H), 1.54 - 1.41 (m, 7 H), 1.31 - 1.13 (m, 7 H), 1.03 (d, J = 6.9 Hz, 6 H), 1.01 (s, 3 H), 0.85 (d, J= 6.1 Hz, 3 H), 0.82 (d, J = 7.6 Hz, 6 H), 0.70 (s, 3 H); ¹³C NMR (100 MHz CDCh) 5 141.3, 138.3, 129.2,

121.3, 57.9 (d, J= 116.35 Hz), 51.2, 50.3, 42.2, 40.5, 40.0, 38.7, 37.4, 36.9, 31.9, 31.9, 29.4, 28.9; ¹⁹F NMR (376 MHz, CDCh) 5 218.

Cholesteryl fluoride (26a): 'H NMR (500 MHz, CDCh) 5 5.38-5.32 (m, 1H), 3.34 - 3.23 (m, 1H), 2.21-2.18 (m, 2H), 2.05-1.93 (m, 2H), 1.85-1.76 (m, 3H), 1.57-1.44 (m, 7H), 1.38-

1.24 (m, 6H), 1.20-1.05 (m, 8H), 1.02 (s, 3H), 0.92 (d, J= 6.5 Hz, 3H), 0.88 (dd, J = 6.5, 1.9 Hz, 6H), 0.69 (s, 3H). ¹³C NMR (125 MHz, CDCh) 5 141.6, 121.6, 76.6, 57.1, 56.4 (d, J = 81.10 Hz), 50.6, 42.6, 40.4, 40.1, 39.8, 37.7, 37.1, 36.5, 36.0, 32.2, 32.2, 29.7, 28.5, 28.4,

24.5. 24.1. 23.1. 22.8. 21.3, 19.7, 19.0, 12.1. ¹⁹F NMR (376 MHz, CDCh) 5 - 79.96.

N4’-3-Fluoropropylciprofloxacin methyl ester(27a) 'H NMR (400MHz, CDCh) 3 8.53 (s, 1H), 8.02 (d, J = 12.8 Hz, 1H), ), 7.28 (d, J = 7.3 Hz, 1H), 4.53 (dt, J = 46.3, 5.6 Hz, 2H), 3.92 (s, 3H), 3.39-3.45 (m, 1H), 3.29-3.30 (m, 4H), 2.66-2.70 (m, 4H), 2.56 (t, J = 14.2 Hz, 2H), 1.89-1.98 (m, 2H), 1.29-1.32 (m, 2H), 1.11-1.15 (m, 2H), ¹³C NMR (100 MHz, CDCh) 3 173.2, 167.5, 153.5 (d, J= 248.1 Hz), 148.3, 144.6 (d, J= 11.5 Hz), 138.2, 124.0 (d, J= 7.0 Hz), 113.4 (d, J= 23.1 Hz), 110.1, 105.8 (d, J= 3.5 Hz), 84.3 (d, J= 163.5 Hz), 55.2 (d, J = 5.7 Hz), 54.1, 52.0, 50.1 (d, J= 4.5 Hz), 34.6, 27.1 (d, J= 20.0 Hz), 8.1; 5-(Fluoromethyl)-2, 2-dimethyltetrahydrofuro [2, 3-d] [1, 3] dioxol-6-ol (28a): H NMR (500 MHz, CDCh) 6.31 (d, J= 3.4 Hz,lH), 5.23 (d, J= 3.7 Hz, 1H), 5.17-5.10 (m, 1H), 4.79- 4.73 (m, 2H), 4.32-4.26 (m, 1H), 1.40 (s, 3H), 1.43 (s, 3H); ¹³C NMR (125 MHz, CDCh) 113.9, 108.2, 87.6, 84.6, 78.3 (d, J = 23.61 Hz), 77.22, 27.9, 27.2; ¹⁹F NMR (376 MHz, CDCh) 5 226.60.

5-((Benzyloxy)methyl)-6-fluoro-2,2-dimethyltetrahydrofuro[2,3-d] [l,3]dioxole (29a) : Synthesized 'H NMR (400 MHz, CDCh) 3 7.37 - 7.32 (m, 5 H), 5.98 (d, J = 3.7 Hz, 1 H), 4.72 - 4.68 (m, 2 H), 4.64 - 4.58 (m, 2 H), 4.49 (s, 2 H), 4.03 (d, J = 3.7 Hz, 1 H), 1.51 (s, 3 H), 1.35 (s, 3 H); ¹³C NMR (100 MHz, CDCH) 5 137.1, 128.5, 128.1, 126.6, 112.0, 105.3, 82.3 (d, J = 20.81 Hz), 81.5 (d, J=5.00 Hz), 80.4, 78.7 (d, J= 81.10 Hz), 72.0, 26.8, 26.3; ¹⁹F NMR (376 MHz, CDCh) - 229.2.

4-(2,2-Dimethyl-l,3-dioxolan-4-yl)-6-fluoro-2,2-dimethyltetrahydrofuro[3,4- d][l,3]dioxole (30a) :

Synthesized according to general procedure: Rr = 0.6 ( 30% EtOAc/hexanes), white solid, 89 % yield, 'H NMR (400 MHz ,CDCh) 3 = 5.76 (d, J = 59.51 Hz), 4.87 (dd, J = 5.53, 3.05 Hz), 4.78 (t, J = 6.1 Hz, 1 H), 4.43 - 4.39 (m, 1 H), 4.17 (dd, J = 3.1, 7.6 Hz, 1 H), 4.15 (dd, 8.39, 4.05 J = 3.14 Hz), 4.09 - (d, J= 6.10, 8.39 Hz), 1.47 (d, J= 2.3 Hz, 6 H), 1.39 (s, 3 H), 1.36 (s, 3 H) ¹³C NMR (100 MHz , CDCh) 5 114.7 (d, J= 241.11 Hz), 114.2, 109.4, 84.9 (d, J = 42.17 Hz), 84.5, 82.6, 78.6, 73.7, 66.6, 26.9, 25.8, 26.1, 24.5; ^/yF NMR (376 MHz, CDCh) - 233.3

1-(4-chlorophenyl)-2-fluoroethan-l-one(31a):, 1H NMR (400 MHz, CDCh) 5 7.88 (d, J = 8.2 Hz, 2 H), 7.48 (d, J = 8.7 Hz, 2 H), 5.49 (d, J = 46.71 Hz, 2H); ¹³C NMR (100 MHz, CDCh) 5 192.6 (d, J = 15.33 Hz), 140.7, 132.1, 128.4 (d, J = 2.88 Hz), 129.3, 84.6 (d, J = 184.03 Hz); ¹⁹F NMR (376 MHz, CDCh) 5 232.60.

2-Fluoro-l-(naphthalen-2-yl)ethan-l-one (32a): 'H NMR (400 MHz, CDCh) 5 8.41 (s, 1H), 8.03-7.94 (m, 3H), 7.93-7.88 (m, 1H), 7.68-7.62 (m, 1H), 7.62-7.56 (m, 1H), 5.73 (s, 1H), 5.62 (s, 1H); ¹³C NMR (100 MHz, CDCh) 5 193.5 (d, J = 15.41 Hz), 136.0, 132.4, 131.0, 129.9, 129.7, 129.6, 129.1, 128.8, 127.9, 127.1, 123.2, 83.6 (d, J = 182.64 Hz); ¹⁹F NMR (376 MHz, CDCh) 5 230.18 l-([l,l'-Biphenyl]-4-yl)-2-fluoroethan-l-one (33a) : *H NMR (400 MHz, CDCh) 5 8.00 (d, J= 8.4 Hz, 2H), 7.74 (d, J= 8.4 Hz, 2H), 7.67 - 7.64 (m, 2H), 7.52 - 7.47 (m, 2H), 7.44 (d, J = 7.6 Hz, 1H), 5.58 (d, J = 46. 54); ¹³C NMR (100 MHz, CDCh) 5 194.0, (d, J = 15.34 Hz) 146.8, 139.5, 133.3, 129.0, 128.5, 128.4, 128.5, 127.2, 127.1; ¹⁹F NMR (376 MHz, CDCh) 5 231.17.

2-fluoro-l-(4-methoxyphenyl)ethan-l-one (34a): 'H NMR (400 MHz, CDCh) 5 7.94 (d, J = 7.9 Hz, 2 H), 7.01 (d, J= 8.5 Hz, 2 H), 5.54 (d, J= 47.00 Hz) 3.88 (s, 3 H); ¹³C NMR (100 MHz CDCh) 5 193.0 (d, J= 15.41 Hz), 164.2, 130.2, 131.2, 126.7, 114.1, 83.3 (d, J= 181.84 Hz), 55.5; ¹⁹F NMR (376 MHz, CDCh) 5 228.8.

2-Fluoro-l-(3-methoxyphenyl)ethan-l-one (35a): 'H NMR (400 MHz, CDCh) 5 7.45 (d, J = 2.3 Hz, 1H), 7.44-7.39 (m, 2H), 7.19-7.15 (m, 1H), 5.53 (d, J = 46.71 Hz, 2H), 3.87 (s, 3H); ¹³C NMR (100 MHz, CDCh) 5 194.1, (d, J = 15.33 Hz), 160.0, 134.9, 129.9, 121.6, 120.6, (d, J = 2.8 Hz), 113. l(d, J = 1.93 Hz), 84.5 (d, J = 182.11 Hz), 55.5; ¹⁹F NMR (376

MHz, CDCh) 5 233.60.

l-fluoro-4-nitrobenzene (36): 'H NMR (400 MHz, CDCh) 5 8.38 - 8.20 (m, 2 H), 7.36 - 7.07 (m, 3 H), ¹³C NMR (100 MHz, CDCh) 5 168.2, 164.6, 144.0, 126.0, 125.9, 116.1, 115.9, 103 ¹⁹F NMR (376 MHz, CDCh) 5 108

Ethyl 2-fluorobenzoate (37): 'H NMR (400 MHz, CDCh) 5 7.95 (dt, J= 1.8, 7.6 Hz, 1 H), 7.55 - 7.48 (m, 1 H), 7.24 - 7.09 (m, 2 H), 4.41 (q, J= 7.1 Hz, 2 H), 1.44 - 1.36 (m, 3 H), ¹³C NMR (100 MHz, CDCh) 5 164.4, 162.2, 160.6, 134.3, 134.2, 132.0, 123.9, 119.1, 119.0, 117.0, 117.8, 61.2, 14.2, ¹⁹F NMR (376 MHz, CDCh) 5 109.

l-(2-fluorophenyl)ethan-l-one(38): 'H NMR (400 MHz, CDCh) 5 7.93 - 7.75 (m, 1 H),

7.63 - 7.44 (m, 1 H), 7.31 - 7.02 (m, 2 H), 2.64 (d, J = 4.9 Hz, 3 H) ¹³C NMR (100 MHz,

CDCh) 5 195.9, 163.5, 160.9, 134.7, 134.6, 130.5, 130.5, 125.7, 125.8, 124.3, 124.3, 116.7, 116.5, 31.4, 31.4, ¹⁹F NMR (376 MHz, CDCh) 5 109.

2-fluorobenzonitrile(39): 'H NMR (400 MHz, CDCh) 5 7.71 - 7.58 (m, 2 H), 7.34 - 7.20 (m, 3 H) ¹³C NMR (100 MHz, CDCh) 5 164.3, 161.7, 136.1, 135.0, 133.4, 124.8, 124.8, 116.5, 116.3, 113.7, 101.4, 101.3, ¹⁹F NMR (376 MHz, CDCh) 5 106.

l-(3-fluorophenyl)ethan-l-one(40): 'H NMR (400 MHz, CDCh) 5 7.78 - 7.69 (m, 1 H), 7.65 - 7.58 (m, 1 H), 7.44 (dt, J = 5.5, 8.0 Hz, 1 H), 7.33 - 7.19 (m, 1 H), 2.58 (s, 3 H), ¹³C NMR (100 MHz, CDCh) 5 196.7, 164.0, 161.6, 139.1, 139.2, 131.3, 130.3, 124.1, 124.1, 120.2, 120.0, 115.0, 115.8, 26.6, ¹⁹F NMR (376 MHz, CDCh) 5 110.

3-fluoro-l,l'-biphenyl (41) *H NMR (400 MHz, CDCh) 5 7.66 - 7.58 (m, 2 H), 7.52 - 7.46 (m, 2 H), 7.47 - 7.37 (m, 3 H), 7.36 - 7.30 (m, 1 H), 7.15 - 7.03 (m, 1 H) ¹³C NMR (100

MHz, CDCh) 5 164.4, 162.0, 143.5, 143.5, 139.9, 131.2, 130.1, 128.9, 128.7, 127.8, 127.8, 127.2, 127.2, 127.1, 123.8, 122.7, 114.1, 113.9, 114.9, ¹⁹F NMR (376 MHz, CDCh) 5 112.

Ethyl 4-fluorobenzoate(42): ¹H NMR (400 MHz, CDCh) 5 8.10 - 8.01 (m, 2 H), 7.11 (t, J = 8.8 Hz, 2 H), 4.37 (q, J = 7.1 Hz, 2 H), 1.41 (t, J = 7.1 Hz, 4 H), ¹³C NMR (100 MHz, CDCh) 5 166.9, 165.6, 164.4, 132.1, 133.0, 126.7, 126.7, 115.5, 115.3, 62.1, 14.3 ¹⁹F NMR (376 MHz, CDCh) 5 106

l,4-difluorobenzene(43): 'H NMR (400 MHz, CDCh) 5 7.03 (t, J = 6.1 Hz, 4 H) ¹³C NMR (100 MHz, CDCh) 5 161.0, 160.0, 157.6, 156.6, 116.5, 116.5, 116.5, 116.3, 116.2, 116.1, ¹⁹F NMR (376 MHz, CDCh) 5 118

(4-fluorophenyl)(phenyl)methanone(44): 'H NMR (400 MHz, CDCh) 5 7.86 - 7.83 (m, 2 H), 7.78 (dd, J= 1.4, 8.2 Hz, 2 H), 7.59 (d, J= 7.8 Hz, 1 H), 7.53 - 7.46 (m, 2 H), 7.16 (t, J = 8.7 Hz, 2 H), ¹³C NMR (100 MHz, CDCh) 5 195.6, 166.9, 164.4, 137.8, 134.1, 134.0, 133.1, 132.9, 132.7, 130.1, 127.7, 128.6, 115.8, 116.6, ¹⁹F NMR (376 MHz, CDCh) 5 105.

2-fluoronaphthalene(45): 'H NMR (400 MHz, CDCh) 5 8.18 - 8.13 (m, 1 H), 7.93 - 7.86 (m, 1 H), 7.67 (d, J = 8.2 Hz, 1 H), 7.62 - 7.54 (m, 2 H), 7.42 (dt, J = 5.5, 7.8 Hz, 1 H), 7.18 (dd, J= 7.8, 10.5 Hz, 1 H) ¹³C NMR (100 MHz, CDCh) 5 161.0, 158.5, 134.9, 134.8, 127.5, 127.5, 126.8, 126.1, 126.6, 125.5, 123.8, 123.6, 122.6, 120.5, 120.5, 109.5, 108.3, ¹⁹F NMR (376 MHz, CDCh) 5 124.

2-fluoropyridine(46): 'H NMR (400 MHz, CDCh) 5 8.25 (d, J = 4.0 Hz, 1 H), 7.85 - 7.68 (m, 1 H), 7.23 - 7.16 (m, 1 H), 6.95 (dd, J= 2.1, 8.3 Hz, 1 H) ¹³C NMR (100 MHz, CDCh) 5 164.7, 162.4, 147.7, 147.5, 141.0, 140.9, 121.1, 122.0, 109.7, 109.3, ¹⁹F NMR (376 MHz,

CDCh) 5 68.

5-Fluoro-N-(4-methoxyphenyl)pentanamide (49): *H NMR (400 MHz, CDCh) 5 7.43-7.40 (m, J = 8.7 Hz, 2H), 6.88-6.86 (m, J = 9.2 Hz, 2H), 4.57 (t, J = 5.5 Hz, 1H), 4.47-4.42 (m, 1H), 3.80 (s, 3H), 2.42 (t, J= 7.3 Hz, 2H), 1.91-1.76 (m, 4H); ¹³C NMR (100 MHz, CDCh) 5

171.5, 156.4, 130.8, 122.7, 114.1, 84.7 (d, J = 163. 54 Hz), 55.6, 36.8, 29.8, (d, J = 19. 33 Hz), 21.7 (d, J = 4. 67 Hz); ¹⁹F NMR (376 MHz, CDCh) 5 217.23.

l-(2-Fluoroethyl)-4-methoxybenzene (52): 'H NMR (400 MHz, CDCh) 5 7.21 (d, J = 8.5 Hz, 2H), 7.04 (d, J= 8.5 Hz, 2H), 4.67 (t, J= 6.7 Hz, 1H), 4.56 (t, J= 6.7 Hz, 1H), 3.82 (s, 3H), 3.08-2.87 (m, 2H); ¹³C NMR (100 MHz, CDCh) 5 158.4, 128.9, 129.1, 129.0, 114.0, 85.2, (d, J= 69. 54 Hz), 55.2, 37.00 (d, J= 20.04 Hz); ¹⁹F NMR (376 MHz, CDCh) 5216.05.

Example 3: General process for desilylation:

Aromatic silane compound was reacted with quaternary ammonium salts of formula la or formula lb at a temperature in the range of 25 to 30°C for a time period in the range of 1 to 4 hours in a tetrahydrofuran solvent to afford desilylation product.

3-(3-((Tert-butyldiphenylsilyl)oxy)propoxy)phenol (55): 'H NMR (400 MHz, CDCh) 5 7.68 (d, J= 7.3 Hz, 4H), 7.45-7.35 (m, 6H), 7.13 (t, J= 8.2 Hz, 1H), 6.49 (d, J= 7.9 Hz, 1H), 6.47-6.38 (m, 2H), 4.10 (t, J= 6.4 Hz, 2H), 3.86 (t, J= 5.8 Hz, 2H), 2.07-1.99 (m, 2H), 1.05 (s, 9H); ¹³C NMR (100 MHz, CDCh) 5 160.4, 156.6, 135.5, 133.7, 131.1, 129.6, 127.6, 107.6, 107.1, 102.0, 65.5, 60.3, 32.2, 29.7, 26.8, 19.2.

3-(3-Hydroxypropoxy)phenol (56): 'H NMR (400 MHz, CDCh) 5 7.12 (t, J= 7.9 Hz, 1H),

6.49 (dd, J= 1.8, 8.5 Hz, 1H), 6.47-6.40 (m, 2H), 4.12 (t, J= 5.8 Hz, 2H), 3.87 (t, J= 5.5 Hz, 2H), 2.07-2.03 (m, 2H); ¹³C NMR (100 MHz, CDCh) 5 160.0, 156.9, 130.2, 108.0, 106.8, 103.0, 65.9, 60.7, 32.8.

ADVANTAGES OF THE INVENTION • Two new quaternary ammonium fluoride salt, with intermolecular hydrogen bonding for the enhanced nucleophilicity of the fluorine is provided.

• The tertiary groups provide a high selectivity in fluorination reaction. The synthesized (di-^tBuOH)2Me2NF fluoride salt offered a good yield of fluorinated products in both SN2 and SNAr fluorination. • Due to the presence of fluorine sources and hydrogen bonding stabilization groups in same salt, no additional additive required.

• Highly stable and low hygroscopicity.

Claims

We claim:

1. A quaternary ammonium fluoride salt selected from formula (la) and formula (lb)

2. A process for the preparation of quaternary ammonium fluoride salts as claimed in claim 1, wherein said process comprises the steps of: a) stirring a mixture of isobutylene oxide, and a respective amine at a temperature in the range of 25 to 50°C for a time period in the range of 70-80 hours to afford a viscous liquid reaction mixture; b) dissolving the reaction mixture of step (a) then adding an alkyl halide and heating at a temperature in the range of 50 to 100°C for 2 to 6 hours to afford a compound containing crystalline solid; c) passing the compound of step (b) through ion exchange resin in a fluorine source from a solvent followed by removing the solvent to afford the quaternary ammonium fluoride salt selected from formula (la) and formula (lb).

3. The process as claimed in claim 2, wherein said amine in step (a) is methyl amine to obtain compound of formula (la) and dimethyl amine to obtain compound of formula (lb).

4. The process as claimed in claim 2, wherein said alkyl halide in step (b) is methyl iodide.

5. The process as claimed in claim 2, wherein said solvent in step (c) is selected from tetrahydrofuran and water, and the flourine source is selected from KF, HF, and NaF.

6. A process for the fluorination of compound of formula (II), wherein said process comprises of stirring the reaction mixture of reactant compound of formula (II), quaternary ammonium fluoride salts selected from compounds of formula (la) or formula (lb) as claimed in claim 1, in a solvent at a temperature in the range of 60°C to 100°C for a time period in the range of 1 to 24 hours to afford fluorinated product of formula (III), wherein the selectivity to the product is at least 70%;

22

X = Leaving Group wherein, R or Ri may be same or different, linear or branched and are selected from the group consisting of hydrogen, alkyl, aryl, alkyl aryl, haloalkyl, hydroxy alkyl, alkoxy, hydroxy, halo, cyano, heteroaryl, heteroalkyl, alkyl heteroaryl, substituted or unsubstituted aryl/alkyl, alkenyl, alkenyl aryl, alkenyl heteroaryl, alkynyl, alkynyl aryl, alkynyl heteroaryl, cycloalkyl, heterocycloalkyl, alkyl cycloalkyl, alkyl heterocycloalkyl, alkyl carboxy, acyl, alkyl acyl, alkyl acyloxy, alkyl alkoxy, alkyl carbonyl, aryl carbonyl, alkoxycarbonyl, alkyl alkoxycarbonyl, aminocarbonyl, alkyl aminocarbonyl, alkyl acylamino, alkyl ureido, amino, alkyl amino, sulfonyloxy, alkyl sulfonyloxy, sulfonyl, alkyl sulfonyl, sulfinyl, alkyl sulfinyl, alkyl sulfanyl and alkyl sulfonylamino;

X is selected from OMs, OTs, OTf, ONs, Cl, Br or I.

7. The process as claimed in claim 6, wherein said compound of formula (II) is further selected from Phenol, Heterocycle, terpene and sugar.

8. The process as claimed in claim 6, wherein said fluorinated product of formula (III) is selected from -(3 -Fluoropropoxy)- l,l'-biphenyl (7a), Alnustin fluoride(8a), Mosloflavone fluoride (9a), Estronfluoride (10a), 8-(Fluoromethyl)hexadecane(l la), 9-(Fluoromethyl)heptadecane (12a), (3 -Fluoropropoxy )benzene (13a), l-(3-

Fluoropropoxy)-2,3-dimethylbenzene (14a), 2-(3 -Fluoropropoxy )naphthalene (15a), l-(3-Fluoropropoxy)-4-methoxybenzene (16a), (3-Fluoropropyl)benzene (17a), 4-(3- Fluoropropoxy)- 1 , 1 '-biphenyl (18a), 4-Bromo-2 -chloro- 1 -(3 -fluoropropoxy )benzene (19a), l-(3-Fluoropropoxy)-lH-benzo[d][l,2,3]triazole (20a), 2 -Benzyl -4-chloro-l- (3-fluoropropoxy)benzene (21a), 4-(3 -Fluoropropoxy )benzonitrile (22a), 9-(2-

Fluoroethyl)-9H-carbazole (23a), l-(3-Fluoropropoxy)-2,3-dimethoxylbenzene(24a) 3-Fluorostigmasterol (25a), Cholesteryl fluoride (26a), N4’-3-

Fluoropropylciprofloxacin methyl ester(27a), 5-(Fluoromethyl)-2, 2- dimethyltetrahydrofuro [2, 3-d][l, 3] dioxol-6-ol (28a), 5-((Benzyloxy)methyl)-6- fluoro-2,2-dimethyltetrahydrofuro[2,3-d][l,3]dioxole (29a),4-(2,2-Dimethyl-l,3- dioxolan-4-yl)-6-fluoro-2,2-dimethyltetrahydrofuro[3,4-d][l,3]dioxole (30a), l-(4- chlorophenyl) -2-fluoroethan- 1 -one(31 a), 2-Fluoro- 1 -(naphthalen-2-yl)ethan- 1 -one

(32a), l-([l,l'-Biphenyl]-4-yl)-2-fluoroethan-l-one (33a), 2-fluoro-l-(4- methoxyphenyl)ethan-l-one (34a), 2-Fluoro-l-(3-methoxyphenyl)ethan-l-one (35a), l-fluoro-4-nitrobenzene (36), ethyl 2-fluorobenzoate(37), l-(2-fluorophenyl)ethan-l- one(38), 2-fluorobenzonitrile (39), l-(3-fluorophenyl)ethan-l-one(40), 3-fluoro-l,l'- biphenyl(41), ethyl 4-fluorobenzoate(42), l,4-difluorobenzene(43), (4- fluorophenyl)(phenyl)methanone(44), 2-fluoronaphthalene (45), 2-fluoropyridine(46), 1 -(4'-fluoro-[ 1 , 1 '-biphenyl] -3 -yl)ethan- 1 -one(47), 5-Fluoro-N-(4- methoxyphenyl)pentanamide (49), l-(2-Fluoroethyl)-4-methoxybenzene (52). The process as claimed in claim 6, wherein said solvent is selected from acetonitrile, dimethylformamide and tert-butyl alcohol. A process for the selective desilylation of aromatic silane group, wherein said process comprises of reacting an aromatic silane compound with the quaternary ammonium salts of formula la or formula lb as claimed in claim 1 at a temperature in the range of 25 to 30°C for a time period in the range of 1 to 4 hours in a tetrahydrofuran solvent to afford desilylation product.