Synthesis of (Fluoroalkyl)amines by Deoxyfluorination of Amino Alcohols

Abstract

Deoxyfluorination of amino alcohols was achieved ­using N,N-diethyl-α,α-difluorobenzylamine (DFBA) to furnish N-benzoyl(fluoroalkyl)amines selectively.

amino alcohols - fluorination - deoxygenation - substitution - N,N-diethyl-α,α-difluorobenzylamine

References and Notes

<A NAME="RU03806ST-1A">1a</A> Coutts RT. Benderly A. Mak ALC. J. Fluorine Chem.  1980,  16:  277 

<A NAME="RU03806ST-1B">1b</A> Kozikowski AP. Wu J.-P. Tetrahedron Lett.  1990,  31:  4309 

<A NAME="RU03806ST-1C">1c</A> Schumacher DP. Clark JE. Murphy BL. Fischer PA. J. Org. Chem.  1990,  55:  5291 

<A NAME="RU03806ST-1D">1d</A> Dolensky B. Kirk KL. J. Org. Chem.  2001,  66:  4687 

<A NAME="RU03806ST-1E">1e</A> Grunewald GL. Romero FA. Criscione KR. J. Med. Chem.  2005,  48:  1806 

<A NAME="RU03806ST-2A">2a</A> Fluorine-Containing Amino Acids   Kukhar VP. Soloshonok VA. Wiley; Chichester: 1995. 

<A NAME="RU03806ST-2B">2b</A> Qiu X.-L. Meng W.-D. Qing F.-L. Tetrahedron  2004,  60:  6711 ; and references cited therein

<A NAME="RU03806ST-3A">3a</A> Chi DY. Kilbourn MR. Katzenellenbogen JA. Welch MJ. J. Org. Chem.  1987,  52:  658 

<A NAME="RU03806ST-3B">3b</A> Lyle TA. Magill CA. Pitzenberger SM. J. Am. Chem. Soc.  1987,  109:  7890 

<A NAME="RU03806ST-3C">3c</A> Posakony JJ. Tewson TJ. Synthesis  2002,  766 

<A NAME="RU03806ST-3D">3d</A> Bolton R. J. Labelled Compd. Radiopharm.  2002,  45:  485 

<A NAME="RU03806ST-3E">3e</A> Couturier O. Luxen A. Chatal J.-F. Vuillez J.-P. Rigo P. Hustinx R. Eur. J. Nucl. Med. Mol. Imaging  2004,  31:  1182 

<A NAME="RU03806ST-4A">4a</A> White GJ. Garst ME. J. Org. Chem.  1991,  56:  3177 

<A NAME="RU03806ST-4B">4b</A> Van Dort ME. Jung Y.-W. Sherman PS. Kilbourn MR. Wieland DM. J. Med. Chem.  1995,  38:  810 

<A NAME="RU03806ST-4C">4c</A> Ok D. Fisher MH. Wyvratt MJ. Meinke PT. Tetrahedron Lett.  1999,  40:  3831 

<A NAME="RU03806ST-4D">4d</A> Posakony JJ. Grierson JR. Tewson TJ. J. Org. Chem.  2002,  67:  5164 

<A NAME="RU03806ST-4E">4e</A> Posakony JJ. Tewson TJ. Synthesis  2002,  766 

<A NAME="RU03806ST-4F">4f</A> McConathy J. Martarello L. Malveaux EJ. Camp VM. Simpson NE. Simpson CP. Bowers GD. Olson JJ. Goodman MM. J. Med. Chem.  2002,  45:  2240 

<A NAME="RU03806ST-5">5</A>

The half-life of ¹⁸F is about 110 min.

<A NAME="RU03806ST-6A">6a</A> Silverman RB. Levy MA. J. Org. Chem.  1980,  45:  815 

<A NAME="RU03806ST-6B">6b</A> Remuzon P. Bouzard D. Di Cesare P. Essiz M. Jacquet JP. Kiechel JR. Ledoussal B. Kesseler RE. Fung-Tomc J. J. Med. Chem.  1991,  34:  29 

<A NAME="RU03806ST-6C">6c</A> Jonghe SD. Overmeire IV. Calenbergh SV. Hendrix C. Busson R. Keukeleire DD. Herdewijn P. Eur. J. Org. Chem.  2000,  3177 

<A NAME="RU03806ST-7">7</A> Ye C. Shreeve JM. J. Fluorine Chem.  2004,  125:  1869 

<A NAME="RU03806ST-8A">8a</A> Kobayashi S. Yoneda A. Fukuhara T. Hara S. Tetrahedron Lett.  2004,  45:  1287 

<A NAME="RU03806ST-8B">8b</A> Kobayashi S. Yoneda A. Fukuhara T. Hara S. Tetrahedron  2004,  60:  6923 

<A NAME="RU03806ST-9">9</A> Yoneda A. Fukuhara T. Hara S. Chem. Commun.  2005,  3589 

<A NAME="RU03806ST-10">10</A> Furuya T. Fukuhara T. Hara S. J. Fluorine Chem.  2005,  126:  721 

<A NAME="RU03806ST-11">11</A> Yu H.-W. Nakano Y. Fukuhara T. Hara S. J. Fluorine Chem.  2005,  126:  962 

<A NAME="RU03806ST-12">12</A>

Due to the enolizable character of the amide function,¹³ the NMR spectra of the N-acylated products 2 were sometimes complicated and reduction of the amide function to the amine was necessary for analysis. When DFBA was used for the reaction with N-benzylamino alcohols, N,N-dibenzylamine derivatives were formed after the reduction, and their NMR spectra are simpler than that of the product from DFMBA. Therefore, DFBA was used instead of DFMBA. DFBA showed reactivity comparable with DFMBA and can be prepared from N,N-diethylbenzamide as DFMBA.¹⁰

<A NAME="RU03806ST-13">13</A> Stewart WE. Siddall TH. Chem. Rev.  1970,  70:  517 

<A NAME="RU03806ST-14">14</A>

To a reactor with a Teflon^TM PFA tube with a diameter of 10 mm sealed at one end, 1a (137 mg, 1 mmol) and DFBA (478 mg, 2.4 mmol) were introduced. The open end of the reactor was connected to a reflux condenser. Then, the reactor part was submitted to microwave-irradiation (IDX microwave oven for organic synthesis IMCR-25003) for 10 min and during the irradiation the temperature was kept at 70 °C. After cooling, the reaction mixture was poured into an aq solution of NaHCO₃. The product was extracted with Et₂O (3 ×) and the combined ethereal layers were dried over MgSO₄. Purification by column chromatography (silica gel, hexane-Et₂O) gave 2a (207 mg, 0.85 mmol) in 85% yield. N -(2-Fluoroethyl)- N -phenylbenzamide ( 2a): IR (neat): 1649, 1494, 1377 cm^-1. ¹H NMR: δ = 7.32-7.09 (m, 10 H), 4.76 (dt, J = 47.6, 4.9 Hz, 2 H), 4.20 (dt, J = 25.6, 4.9 Hz, 2 H). ¹⁹C NMR: δ = 170.94, 144.08, 135.80, 129.94, 129.31 (2 C), 128.90 (2 C), 127.89 (2 C), 127.83 (2 C), 126.91, 81.52 (d, J = 168.7 Hz), 51.57 (d, J = 20.7 Hz). ¹⁹F NMR: δ = -222.60 to -222.98 (m, 1 F). HRMS (EI): m/z calcd for C₁₅H₁₄NOF: 243.1059; found: 243.1057. ( S )-1-Fluoro-2-aminopropane Hydrochloride ( S )-(5)·HCl: White solid; mp 123-124 °C (lit.^4e 127-127.5 °C); [α]_D ²¹ +12.4 (c 1.01, MeOH) {lit.^4e [α]_D ²³ +12.7 (c 1.01, MeOH)}. (R)-MTPA amide of ( S )-5 ¹⁹F NMR: δ = -69.54 (s, 3 F), -232.36 (dt, J = 26.2, 47.0 Hz, 1 F). ( R )-1-Fluoro-2-aminopropane Hydrochloride ( R )-(5)·HCl: White solid; mp 123-124.5 °C (lit.^4e 127-128 °C); [α]_D ²² -13.7 (c 1.00, MeOH) {lit.^4e [α]_D ²³ -14.9 (c 1.10, MeOH)}. (R)-MTPA amide of ( R )-5; ¹⁹F NMR: δ = -69.47 (s, 3 F), -232.73 (dt, J = 26.2, 47.0 Hz, 1 F).

<A NAME="RU03806ST-15">15</A> Charvillon FB. Amouroux R. Tetrahedron Lett.  1996,  37:  5103