Synthesis of 3-Aminomethyl-3-fluoropiperidines

Abstract

A synthetic route toward new 1-alkyl-3-aminomethyl-3-fluoropiperidines, which are of high interest as building blocks in medicinal chemistry, is described. The successful approach consists of the fluorination of ethyl 3-chloropropyl-2-cyanoacetate with N-fluorodibenzenesulfonimide (NFSI) and transformation of the ester moiety into different amides, yielding N-alkyl-5-chloro-2-cyano-2-fluoropentanamides. Ring closure was achieved under basic conditions, yielding 1-alkyl-3-fluoro-2-oxopiperidine-3-carbonitriles. After reduction of the obtained lactams with borane, the desired 3-aminomethyl-3-fluoropiperidines were obtained in good yields.

The beneficial effects of fluorine as a substituent in organic compounds stimulated intense research into organo­fluorine chemistry during the last decade. This is reflected by the numerous papers in this area in recent years and the commercial applications of organofluorine compounds in pharmaceutical chemistry and agrochemistry. [²-8] More specifically, fluorinated heterocycles attract widespread attention as important components of agrochemicals and pharmaceuticals. [9] 3-Fluoropiperidines 1 are recognised as T-type calcium channel antagonists and are useful in the treatment and prevention of neurological and psychiatric disorders (Figure  [¹] ). [¹0]

Only a limited number of synthetic routes toward these interesting 3-fluoropiperidines are available. [¹¹] One method proceeds via α-fluorination of 4-piperidone [¹²] followed by TfOH-catalyzed double electrophilic substitution to benzene resulting in 3-fluoro-2,2-diphenylpiperidine. [¹³] Recently, the synthesis of a wide range of optically active 3-fluoropiperidines was developed starting from prolinols by treatment with DAST or Deoxo-Fluor^TM. [¹4] Nonetheless, access to 3-aminomethyl-3-fluoropiperidines is not available, although these compounds are of high interest since they can easily be incorporated into compounds ­of pharmaceutical interest. Here, a general route to 1-alkyl- and 1-arylmethyl-3-aminomethyl-3-fluoropiperi-dines starting from ethyl cyanoacetate is described.

In a first step, various attempts were made to synthesize 5-halo-2-cyanopentanoates as starting material for the synthesis of the desired 3-fluoropiperidines. Because the direct fluorination of ethyl cyanoacetate using NFSI resulted in mixtures of mono- and difluorinated compounds, it was decided to alkylate cyanoacetate 2 first and subsequently fluorinate the obtained alkylated cyanoacetate 3. At first, the chloroalkylation of ethyl cyanoacetate (2) was performed by reaction with one equivalent of K₂CO₃ and one equivalent of 1-bromo-3-chloropropane at room temperature in DMF. After 18 hours, the reaction mixture was analyzed by GC-MS, to reveal that a mixture of starting material 2 (8%), ethyl 5-chloro-2-cyanopentanoate (3; 43%) and the corresponding dialkylated ­cyanoacetate 4 (49%) was obtained. In no cases could ­selective monoalkylation be achieved when using equimolar quantities of ethyl cyanoacetate, base and either 1-bromo-3-chloropropane or 3-chloro-1-iodopropane. However, the reaction of three equivalents of ­cyanoacetate and three equivalents of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) with one equivalent of 3-chloro-1-iodopropane at 10 ˚C in benzene yielded predominantly monoalkylated cyanoacetate 3, together with unreacted starting material 2.

Indeed, it is known that the use of DBU in benzene can be successful for the monoalkylation reactions of cyanoacetates. [¹5] GC-analysis of the crude reaction mixture ­revealed a product ratio of ethyl 5-chloro-2-cyanopentanoate (3) to the corresponding dialkylation product 4 of 5 to 1, respectively. From this mixture, 5-chloro-2-cyanopentanoate (3) could be easily separated by fractional distillation (106-110 ˚C) under reduced pressure (1.5 mmHg), yielding pure cyanopentanoate 3 in 50% yield (based on the recovery of the starting material, Scheme  [¹] ). Although a low yield was obtained, the ease of the reaction, combined with the easy separation of compound 3, resulted in a straightforward, multi-gram scale preparation of up to 5 g of the desired starting material. Although a selective monoalkylation of ethyl cyanoacetate with 1,3-dibromopropane in DMF, in the presence of 2.5 equivalents of K₂CO₃, has been described rather recently for the synthesis of ethyl 5-bromo-2-cyanopentanoate 5, [¹5] in our hands, this reaction (with or without the presence of the catalytic imidazolium salt 1-butyl-3-methylimidazolium tetrafluoroborate) always gave rise to the formation of the corresponding substituted cyclobutane 6 [¹6] (Scheme  [²] ).

The problematic selective monoalkylation of ethyl cyanoacetate (2) has already been discussed in the literature, where the use of masking groups for one of the acidic hydrogens is deviced. [¹7]

In a next step, the fluorination of ethyl 5-chloro-2-cyanopentanoate (3) using 1.2 equivalents of N-fluorodiben­zenesulfonimide (NFSI) and 1.2 equivalents of K₂CO₃ in DMF at room temperature during 20 hours, nicely gave rise to the corresponding fluorinated cyanopentanoate 7 in 71% yield. The material was sufficiently pure for further use in the next step (purity of 7: 85%). The reaction of 7 with N-alkyl- and N-arylmethylamines resulted in the formation of α-fluorinated amides 8a-d, which were subjected to ring closure conditions. The reaction of 8a-d with 1.2 equivalents of K₂CO₃ in DMSO during one hour gave rise to 1-alkyl-3-fluoro-2-oxopiperidine-3-carbonitriles 9a-d, after purification by flash chromatography on silica gel.

These piperidones 9 proved to be good substrates for reduction by borane in THF to give the desired 1-alkyl-3-aminomethyl-3-fluoropiperidines 10a-d. Purification of the obtained piperidines could be performed in an elegant way via precipitation from diethyl ether as the trifluoroacetic acid salts, followed by filtration of the white crystalline salts. After treatment with aqueous NaHCO₃ and extraction, pure 3-aminomethyl-3-fluoropiperidines 10a-d were obtained (Scheme  [³] ).

It should be noted that the cyclization reaction conditions used to synthesize lactams 9 need to be performed in anhydrous solvents, as the presence of water gives rise to varying yields of cyclization product 11 (Scheme  [4] ). As an example, when compound 8a was reacted with t-BuOK in wet THF (i.e. not dried over sodium benzophenone ketyl) at room temperature, significant hydrolysis of the nitrile function occurred, giving rise to a mixture of lactams 11 and 9a (Scheme  [4] ).

In conclusion, a straightforward synthesis of 3-amino­methyl-3-fluoropiperidines was designed, yielding new 1-alkyl and 1-arylmethyl-3-aminomethyl-3-fluoropiperidines, starting from ethyl cyanoacetate, in moderate to good yields. This five-step procedure is a convenient route for the large-scale preparation of 3-aminomethyl-3-fluoropiperidines 10, which are compounds with high potential as building blocks in medicinal chemistry.

Ethyl 5-Chloro-2-cyanopentanoate (3)

To a solution of ethyl cyanoacetate (17.0 g, 0.15 mol) and DBU (22.8 g, 0.15 mol) in anhydrous benzene (500 mL), was added a solution of 3-chloro-1-iodopropane (10.2 g, 0.05 mol) in benzene (50 mL) at 10 ˚C during 30 min. After stirring for 10 h at 10 ˚C, the resulting yellow reaction mixture was poured into H₂O (300 mL) and extracted with Et₂O (5 × 100 mL). The combined organic phases were washed with brine (3 × 200 mL) and dried over MgSO₄. After filtration of the drying agents and evaporation of the solvents, the crude mixture was fractionally distilled, yielding starting material 2 (7.81 g; bp 45-50 ˚C at 1.0 mbar) and ethyl 5-chloro-2-cyanopentanoate (3; 7.60 g; bp 81-85 ˚C at 0.6 mmHg). Yield: 50% (based on the recovery of the starting material); colourless oil. ^¹H NMR (300 MHz, CDCl₃): δ = 1.34 (3 H, t, J = 7.2 Hz, CH₃), 1.92-2.24 (4 H, m, ClCH₂CH ₂CH ₂CF), 3.56-3.63 (3 H, m, CH₂Cl and CHCN), 4.28 (2 H, q, J = 7.2 Hz, CH ₂CH₃). ^¹³C NMR (75 MHz, CDCl₃, int. ref.: 77.4 ppm): δ = 14.1 (CH₃), 27.3 (CH₂CH₂Cl or CH₂CH), 29.5 (CH₂CH or CH₂CH₂Cl), 37.0 (CH), 43.7 (CH₂Cl), 63.2 (CH₃ CH₂), 116.3 (CN), 165.9 (C=O). IR (NaCl): 2985, 2251 (ν_CN), 1745 (ν_CO), 1448, 1370 cm^-¹. MS (ES-): m/z (%) = 189/91 ­(M - H⁺, 100/31). Anal. Calcd. for C₈H₁₂ClNO₂: C, 50.7; H, 6.4; N, 7.4. Found: C, 50.6; H, 6.3; N, 7.3.

5-Chloro-2-cyano-2-fluoropentanoate (7)

To a solution of ethyl 5-chloro-2-cyanopentanoate (3; 2.0 g, 10.6 mmol) and K₂CO₃ (1.6 g, 11.6 mmol) in DMF (40 mL) in a 100 mL flask, was added N-fluorodibenzenesulfonimide (NFSI) (4.0 g, 12.7 mmol, 1.1 equiv). After stirring the reaction mixture for 20 h and filtration of the solids, the filtrate was poured into H₂O (30 mL) and extracted with Et₂O (3 × 30 mL). The combined organic phases were washed with brine (3 × 20 mL) and subsequently dried over MgSO₄. Filtration of the drying agents and evaporation of the solvent yielded ethyl 5-chloro-2-cyano-2-fluoropentanoate (7), which was sufficiently pure for further use in the next step. Yield: 1.55 g (71%); purity: 85%. For analytical purposes, a sample was purified by flash chromatography over silica gel (EtOAc-hexane, 9:1; R _f  = 0.45). Yield: 58%; colourless oil. ^¹H NMR (300 MHz, CDCl₃): δ = 1.39 (3 H, t, J = 7.2 Hz, CH₃), 1.95-2.19 (2 H, m, ClCH₂CH ₂), 2.27-2.47 (2 H, m, CFCH₂), 3.62 (2 H, t, J = 6.2 Hz, CH₂Cl), 4.40 (2 H, q, J = 7.2 Hz, CH ₂CH₃). ^¹³C NMR (75 MHz, CDCl₃): δ = 14.0 (CH₃), 26.2 (d, J = 2.3 Hz, CH₂CH₂Cl), 34.5 (d, J = 23.1 Hz, CH₂CF), 43.3 (CH₂Cl), 64.4 (CH₂O), 86.5 (d, J = 196.1 Hz, CF), 113.9 (d, J = 34.6 Hz, CN), 163.2 (d, J = 26.5 Hz, C=O). ^¹9F NMR (282 MHz, CDCl₃): δ = -158.61 (1 F, t, J = 6.2 Hz). IR (NaCl): 2987, 2253 (ν_CN), 1773 (ν_CO), 1583, 1451, 1400 cm^-¹. GC-MS (EI): m/z (%) = 207/9 (M+, 0.01/0.003), 162 (M+, 5), 135 (36), 100 (61), 72 (100).

N -Benzyl-5-chloro-2-cyano-2-fluoropentanamide (8a); Typical Procedure

The synthesis of amide 8a is given as a representative example for the synthesis of amides 8a-d. A solution of ethyl 5-chloro-2-cyano-2-fluoropentanoate (7; 3.3 g, 16 mmol) and benzylamine (1.7 g, 16 mmol) in dichloromethane (40 mL) was stirred for 5 h at r.t.. Evaporation of the solvent yielded the crude N-benzyl-5-chloro-2-cyano-2-fluoropentanamide (8a). Purification was performed by flash chromatography over silica gel (EtOAc-hexane, 9:1; R _f  = 0.01), yielding pure N-benzyl-5-chloro-2-cyano-2-fluoropentanamide. Yield: 2.51 g (57%); viscous colourless oil. ^¹H NMR (300 MHz, CDCl₃): δ = 1.92-2.15 (2 H, m, ClCH₂CH ₂), 2.26-2.53 (2 H, m, CFCH₂), 3.57 (2 H, t, J = 6.3 Hz, CH₂Cl), 4.49 (2 H, d, J = 5.8 Hz, CH ₂NH), 6.85 (1 H, s, NH), 7.26-7.40 (5 H, m, 5 × CH_ar). ^¹³C NMR (75 MHz, CDCl₃, int. ref.: 77.4 ppm): δ = 26.3 (d, J = 2.3 Hz, CH₂CH₂Cl), 34.5 (d, J = 21.9 Hz, CH₂CF), 43.4 (CH₂Cl), 43.9 (CH₂NH), 89.3 (d, J = 199.6 Hz, CF), 114.4 (d, J = 33.5 Hz, CN), 127.8 (2 × CH_ar), 128.1 (CH_ar), 129.0 (2 × CH_ar), 136.6 (C_q,ar), 163.1 (d, J = 21.9 Hz, C=O). ^¹9F NMR (282 MHz, CDCl₃): δ = -158.74 (1 F, t, J = 23.7 Hz). IR (NaCl): 3336 (ν_NH), 2253 (ν_CN), 1689 (ν_CO), 1539, 1444 cm^-¹. MS (ES+): m/z (%) = 286/8 (M + NH₄ ⁺, 100/32). Anal. Calcd. for C₁₃H₁₄ClFN₂O: C, 58.1; H, 5.3; N, 10.4. Found: C, 58.0; H, 5.1; N, 10.2.

1-Benzyl-3-fluoro-2-oxopiperidine-3-carbonitrile (9a); Typical Procedure

The synthesis of 1-benzyl-3-fluoro-2-oxopiperidine-3-carbonitrile (9a) is given as a representative example for the synthesis of 1-alkyl-3-fluoro-2-oxopiperidine-3-carbonitriles 9a-d. A solution of N-benzyl-5-chloro-2-cyano-2-fluoropentanamide (8a; 0.27 g, 16 mmol) and K₂CO₃ (2.6 g, 19 mmol, 1.2 equiv) in DMSO (20 mL) was heated under reflux for 1 h. The resulting mixture was poured into H₂O (10 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic layers were dried (MgSO₄) and, after evaporation of the solvent, crude 1-benzyl-3-fluoro-2-oxopiperidine-3-carbonitrile (9a) was obtained. Purification was performed by flash chromatography over silica gel (EtOAc-hexane, 8:2; R _f  = 0.14) to give 1-benzyl-3-fluoro-2-oxopiperidine-3-carbonitrile (9a). Yield: 2.05 g (54%); white crystals; mp 53 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.90-2.14 (2 H, m, CH ₂CH₂N), 2.46 (2 H, dt, J = 6.2 Hz, J = 17.3 Hz, CH₂CF), 3.30 (2 H, dt, J = 6.1 Hz, J = 1.2 Hz, CH₂CH ₂N), 4.55 (1 H, d, J = 14.6 Hz, NCH _aH_b), 4.67 (1 H, d, J = 14.6 Hz, NCH_a H _b), 7.18-7.38 (5 H, m, 5 × CH_ar). ^¹³C NMR (75 MHz, CDCl₃, int. ref.: 77.4 ppm): δ = 18.0 (d, J = 4.6 Hz, CH₂CH₂N), 32.9 (d, J = 23.1 Hz, CH₂CF), 46.6 (CH₂ CH₂N), 51.1 (C_q,arCH₂), 84.6 (d, J = 188.1 Hz, CF), 115.6 (d, J = 35.8 Hz, CN), 128.1 (CH_ar), 128.3 (2 × CH_ar), 129.0 (2 × CH_ar), 135.2 (C_q,ar), 160.0 (d, J = 23.1 Hz, C=O). ^¹9F NMR (282 MHz, CDCl₃): δ = -148.87 (1 F, t, J = 17.8 Hz). IR (KBr): 3400, 2239 (ν_CN), 1673 (ν_CO), 1496, 1455 cm^-¹. MS (ES+): m/z (%) = 250 (M + NH₄ ⁺, 100), 233 (M + H⁺, 31).

3-Aminomethyl-1-benzyl-3-fluoropiperidine (10a); Typical Procedure

The synthesis of 3-aminomethyl-1-benzyl-3-fluoropiperidine (10a) is given as a representative example for the synthesis of 1-alkyl-3-aminomethyl-3-fluoropiperidines 10a-d. To a solution of 1-butyl-3-fluoro-2-oxopiperidine-3-carbonitrile (9a; 0.19 g, 0.8 mmol) in THF (10 mL) under a nitrogen atmosphere, was added carefully BH₃ (1 M in THF, 4 mL, 4 mmol, 5 equiv). After stirring for 16 h at r.t., MeOH was carefully added until the evolution of hydrogen gas stopped. This mixture was stirred for 1 h at r.t., and subsequently, the solvents were evaporated. The crude mixture was taken up in Et₂O (3 mL), and 1 M HCl (1 mL) was added. The organic layer was extracted with 1 M HCl (2 × 3 mL) and the combined aqueous layers were then neutralized to pH 7 with 1 M NaOH and extraction was performed with EtOAc (3 × 5 mL). Drying (MgSO₄), filtration and evaporation of the solvent yielded the crude 3-aminomethyl-1-butyl-3-fluoropiperidine (10a), which was purified by dissolving the piperidine in anhydrous Et₂O, and adding an excess of trifluoroacetic acid (0.5 mL). After stirring for 16 h at r.t., the precipitated ­3-aminomethyl-1-benzyl-3-fluoropiperidine trifluoroacetate was filtered and dried at high vacuum. Yield: 70%; white crystals; mp 175 ˚C. ^¹H NMR (300 MHz, D₂O): δ = 1.52-1.76 (1 H, m, CH₂CH _aH_bCF), 1.86-2.01 (2 H, m, CH ₂CH₂CF), 2.02-2.16 (1 H, m, CH₂CH_a H _bCF), 2.90-3.06 (1 H, m, NCH _aH_bCH₂), 3.16-3.32 (3 H, m, NCH _a H _bCF and CH ₂NH₂), 3.42-3.61 (2 H, m, NCH_a H _bCH₂ and NCH_a H _bCF), 4.27 (1 H, d, J = 13.2 Hz, CH _aH_bC_q,ar), 4.36 (1 H, d, J = 13.2 Hz, CH_a H _bC_q,ar), 7.35-7.48 (5 H, m, 5 × CH_ar). ^¹³C NMR (75 MHz, D₂O): δ = 17.7 (CH₂CH₂N), 27.8 (d, J = 20.8 Hz, CH₂ CH₂CF), 44.1 (d, J = 19.6 Hz, CH₂NH₂), 51.5 (CH₂ CH₂N), 54.4 (d, J = 21.9 Hz, CFCH₂N), 61.1 (C_q,ar CH₂), 91.0 (d, J = 177.7 Hz, CF), 116.5 (q, J = 291.9 Hz, CF₃), 127.8 (C_q,ar), 129.4 (2 × CH_ar), 130.5 (CH_ar), 131.6 (2 × CH_ar), 163.0 (q, J = 35.4 Hz, C=O). ^¹9F NMR (282 MHz, D₂O): δ = -165.39 (br s, 1 F, CF), -75.38 (br s, 3 F, CF₃). IR (KBr): 3400, 3013, 1677 (ν_CO), 1429, 1203 cm^-¹. MS (ES+): m/z (%) = 223 (M + H⁺, 100). In order to obtain the free amine, the obtained TFA salt was treated with sat. aq NaHCO₃ (3 mL) and extracted with EtOAc (3 × 3 mL). The combined organic layers were dried (MgSO₄), filtered and, after evaporation of the solvent, pure 3-aminomethyl-1-benzyl-3-fluoropiperidine (10a) was obtained. Yield: 0.10 g (82%); colourless liquid. ^¹H NMR (300 MHz, CDCl₃): δ = 1.44-1.85 (6 H, m, NH₂ and CH₂CH ₂CF and CH ₂CH₂CF), 2.31-2.54 (4 H, m, CH₂CH ₂CF and NCH ₂CH₂), 2.73-2.97 (2 H, m, CH ₂NH₂), 3.50 (1 H, d, J = 13.2 Hz, CH _aH_bC_q,ar), 3.59 (1 H, d, J = 13.2 Hz, CH_a H _bC_q,ar), 7.21-7.34 (5 H, m, 5 × CH_ar). ^¹³C NMR (75 MHz, CDCl₃, int. ref.: 77.4 ppm): δ = 22.5 (d, J = 6.9 Hz, CH₂CH₂N), 31.7 (d, J = 20.8 Hz, CH₂ CH₂CF), 48.2 (d, J = 23.1 Hz, CH₂NH₂), 53.6 (CH₂ CH₂N), 58.3 (d, J = 24.2 Hz, CFCH₂N), 63.0 (C_q,ar CH₂), 94.8 (d, J = 171.9 Hz, CF), 127.4 (CH_ar), 128.6 (2 × CH_ar), 129.2 (2 × CH_ar), 138.3 (C_q,ar). ^¹9F NMR (282 MHz, CDCl₃): δ = -160.81 (br s, 1 F, CF). IR (NaCl): 3393, 2943, 1683, 1454 cm^-¹. MS (ES+): m/z (%) = 223 (M + H⁺, 100).

Acknowledgment

The authors are indebted to the Research Foundation - Flanders (FWO-Flanders), Ghent University (GOA, BOF) and Johnson&Johnson Pharmaceutical Research & Development, a Division of Janssen Pharmaceutica NV, for financial support.

References and Notes

• For examples, see:
• 2a Papeo GME, Caronni D, Dalvit C, Giordano P, Mongelli N, Veronesi M, and Ciprandi F. inventors; Eur. Pat. Appl. EP  1923397.  ; A1 20080521
• 2b Grabstein KH, Wang A, Nairn N, Winblade G, and Thomas J. inventors; U.S. Pat. Appl. Publ. US  2008096819.  ; A1 20080424
• 2c Edmondson SD. Mastracchio A. Mathvink RJ. He J. Harper B. Park Y.-J. Beconi M. Di Salvo J. Eiermann GJ. He H. Leiting B. Leone JF. Levorse DA. Lyons K. Patel RA. Patel SB. Petrov A. Scapin G. Shang J. Roy RS. Smith A. Wu JK. Xu S. Zhu B. Thornberry NA. Weber AE. J. Med. Chem.  2006,  49:  3614 
  Search in Google Scholar
• 2d Celanire S, Quere L, Denonne F, and Provins L. inventors; PCT Int. Appl. WO  2007048595.  ; A1 20070503
• 2e Keith JM. Gomez LA. Letavic MA. Ly KS. Jablonowski JA. Seierstad M. Barbier AJ. Wilson SJ. Boggs JD. Fraser IC. Mazur C. Lovenberg TW. Carruthers NI. Bioorg. Med. Chem. Lett.  2007,  17:  702 
  Search in Google Scholar
• 2f Parker JC, and Hulin B. inventors; US Pat. Appl. Publ. US  2005043292.  ; A1 24/02/2005; Chem. Abstr. 2005, 142, 261783
• 3a Fluorine in Bioorganic Chemistry   Welch JT. Eswarakrishnan S. Wiley-Interscience; New York: 1991. 
• 3b Bioorganic and Medicinal Chemistry of Fluorine   Bégué JP. Bonnet-Delpon D. John Wiley & Sons, Inc.; New Jersey: 2008. 
• 4 Hagmann WK. J. Med. Chem.  2008,  51:  4359 
  CrossrefPubMedSearch in Google Scholar
• 5 O" Hagan D. Chem. Soc. Rev.  2008,  37:  308 
  CrossrefSearch in Google Scholar
• 6 Purser S. Moore PR. Swallow S. Gouverneur V. Chem. Soc. Rev.  2008,  37:  320 
  CrossrefPubMedSearch in Google Scholar
• 7 Kirk KL. Org. Process Res. Dev.  2008,  12:  305 
  CrossrefSearch in Google Scholar
• 8 Müller K. Faeh C. Diederich F. Science  2007,  317:  1881 
  CrossrefPubMedSearch in Google Scholar
• 9 Differding E. Frick W. Lang RW. Martin P. Schmit C. Veenstra S. Greuter H. Bull. Soc. Chim. Belg.  1990,  99:  647 
  Search in Google Scholar
• 10 inventors; Barrow J. C., Lindsley C. W., Shipe W. D., Yang Z.: PCT Int. Appl.  WO/2007/002361.  ; Chem. Abstr. 2007, 146, 121830
• 11 Verniest G. Surmont R. Van Hende E. Deweweire A. Deroose F. Thuring JW. De Kimpe N. J. Org. Chem.  2008,  73:  5458 
  CrossrefPubMedSearch in Google Scholar
• 12 Van Niel MB. Collins I. Beer MS. Broughton HB. Cheng SKF. Goodacre SC. Heald A. Locker KL. MacLeod AM. Morrison D. J. Med. Chem.  1999,  42:  2087 
  CrossrefPubMedSearch in Google Scholar
• 13 Sun A. Lankin DC. Hardcastle K. Snyder JP. Chem. Eur. J.  2005,  11:  1579 
  CrossrefSearch in Google Scholar
• 14 Dechamps I. Gomez Pardo D. Cossy J. Eur. J. Org. Chem.  2007,  4224 
  Crossref
• 15a Ono N. Yoshimura T. Saito T. Tamura R. Tanikaga R. Kaji A. Bull. Chem. Soc. Jpn.  1979,  52:  1716 
  Search in Google Scholar
• 15b Muthusamy S. Gnanaprakasam B. Tetrahedron Lett.  2005,  46:  635 
  Search in Google Scholar
• 16 Zefirov NS. Kuznetsova TS. Kozhushkov SI. Surmina LS. Rashchupkina ZA. Zh. Org. Khim.  1983,  19:  541 
  Search in Google Scholar
• 17 Grossman RB. Varner MA. J. Org. Chem.  1997,  62:  5235 
  CrossrefSearch in Google Scholar

Postdoctoral Fellow of the Research Foundation - Flanders (FWO-Vlaanderen)

References and Notes

• For examples, see:
• 2a Papeo GME, Caronni D, Dalvit C, Giordano P, Mongelli N, Veronesi M, and Ciprandi F. inventors; Eur. Pat. Appl. EP  1923397.  ; A1 20080521
• 2b Grabstein KH, Wang A, Nairn N, Winblade G, and Thomas J. inventors; U.S. Pat. Appl. Publ. US  2008096819.  ; A1 20080424
• 2c Edmondson SD. Mastracchio A. Mathvink RJ. He J. Harper B. Park Y.-J. Beconi M. Di Salvo J. Eiermann GJ. He H. Leiting B. Leone JF. Levorse DA. Lyons K. Patel RA. Patel SB. Petrov A. Scapin G. Shang J. Roy RS. Smith A. Wu JK. Xu S. Zhu B. Thornberry NA. Weber AE. J. Med. Chem.  2006,  49:  3614 
  Search in Google Scholar
• 2d Celanire S, Quere L, Denonne F, and Provins L. inventors; PCT Int. Appl. WO  2007048595.  ; A1 20070503
• 2e Keith JM. Gomez LA. Letavic MA. Ly KS. Jablonowski JA. Seierstad M. Barbier AJ. Wilson SJ. Boggs JD. Fraser IC. Mazur C. Lovenberg TW. Carruthers NI. Bioorg. Med. Chem. Lett.  2007,  17:  702 
  Search in Google Scholar
• 2f Parker JC, and Hulin B. inventors; US Pat. Appl. Publ. US  2005043292.  ; A1 24/02/2005; Chem. Abstr. 2005, 142, 261783
• 3a Fluorine in Bioorganic Chemistry   Welch JT. Eswarakrishnan S. Wiley-Interscience; New York: 1991. 
• 3b Bioorganic and Medicinal Chemistry of Fluorine   Bégué JP. Bonnet-Delpon D. John Wiley & Sons, Inc.; New Jersey: 2008. 
• 4 Hagmann WK. J. Med. Chem.  2008,  51:  4359 
  CrossrefPubMedSearch in Google Scholar
• 5 O" Hagan D. Chem. Soc. Rev.  2008,  37:  308 
  CrossrefSearch in Google Scholar
• 6 Purser S. Moore PR. Swallow S. Gouverneur V. Chem. Soc. Rev.  2008,  37:  320 
  CrossrefPubMedSearch in Google Scholar
• 7 Kirk KL. Org. Process Res. Dev.  2008,  12:  305 
  CrossrefSearch in Google Scholar
• 8 Müller K. Faeh C. Diederich F. Science  2007,  317:  1881 
  CrossrefPubMedSearch in Google Scholar
• 9 Differding E. Frick W. Lang RW. Martin P. Schmit C. Veenstra S. Greuter H. Bull. Soc. Chim. Belg.  1990,  99:  647 
  Search in Google Scholar
• 10 inventors; Barrow J. C., Lindsley C. W., Shipe W. D., Yang Z.: PCT Int. Appl.  WO/2007/002361.  ; Chem. Abstr. 2007, 146, 121830
• 11 Verniest G. Surmont R. Van Hende E. Deweweire A. Deroose F. Thuring JW. De Kimpe N. J. Org. Chem.  2008,  73:  5458 
  CrossrefPubMedSearch in Google Scholar
• 12 Van Niel MB. Collins I. Beer MS. Broughton HB. Cheng SKF. Goodacre SC. Heald A. Locker KL. MacLeod AM. Morrison D. J. Med. Chem.  1999,  42:  2087 
  CrossrefPubMedSearch in Google Scholar
• 13 Sun A. Lankin DC. Hardcastle K. Snyder JP. Chem. Eur. J.  2005,  11:  1579 
  CrossrefSearch in Google Scholar
• 14 Dechamps I. Gomez Pardo D. Cossy J. Eur. J. Org. Chem.  2007,  4224 
  Crossref
• 15a Ono N. Yoshimura T. Saito T. Tamura R. Tanikaga R. Kaji A. Bull. Chem. Soc. Jpn.  1979,  52:  1716 
  Search in Google Scholar
• 15b Muthusamy S. Gnanaprakasam B. Tetrahedron Lett.  2005,  46:  635 
  Search in Google Scholar
• 16 Zefirov NS. Kuznetsova TS. Kozhushkov SI. Surmina LS. Rashchupkina ZA. Zh. Org. Khim.  1983,  19:  541 
  Search in Google Scholar
• 17 Grossman RB. Varner MA. J. Org. Chem.  1997,  62:  5235 
  CrossrefSearch in Google Scholar

Postdoctoral Fellow of the Research Foundation - Flanders (FWO-Vlaanderen)