- Email: [email protected]
[3 + 2] Cycloaddition reactions of ethyl (Z)-3-fluoropropenoate with nitrones
Journal of Fluorine Chemistry 155 (2013) 59–61
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry journal homepage: www.elsevier.com/locate/fluor
[3 + 2] Cycloaddition reactions of ethyl (Z)-3-fluoropropenoate with nitrones Timothy B. Patrick *, Akbar H. Khan Department of Chemistry, Southern Illinois University, Edwardsville, IL, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 5 March 2013 Received in revised form 26 April 2013 Accepted 8 May 2013 Available online 27 May 2013
Ethyl (Z)-2-fluoropropenoate reacts stereospecifically and regioselectively in [3 + 2] cycloadditions with aryl N-methylnitrones. The yields of the cycloaddition products range from 61 to 70%. ß 2013 Elsevier B.V. All rights reserved.
Keywords: Ethyl (Z)-2-fluoropropenoate Fluoro-isoxazolidines Aryl N-methylnitrone [3 + 2] Cycloadditions
1. Introduction Cycloaddition reactions of fluorinated alkenes represent an important new methodology for the preparation of fluorinated carbocycles [1,2] and fluorinated heterocycles. [3]. Following our studies of Diels–Alder cycloadditons and [3 + 2] cycloadditions of diethyl (E)-fluoromaleates (1) [4,5], we now extend our research to include [3 + 2] cycloadditions of ethyl (Z)fluoropentenoate (2) [5]. Although Huisgen’s methodology is long known [6], very little is reported on the preparation of ringfluorinated heterocycles by [3 + 2] cyclizations [2].
compounds with applications in biological sciences. We have already reported that cycloadditions with 1 and nitrones occurs readily in a concerted manner [5]. This paper describes our reactions between 2 and nitrones and an NMR study of the reaction stereochemistry. 2. Results and discussion Both the preparation of 2 [4] and the aromatic nitrones 3a, 3b, 3c, 3d, 3e and 3f have been described by us previously [5].
The concept of [3 + 2] cycloaddition reactions was reviewed in 1963 by Huisgen [6]. Many new materials with widespread biological use have been prepared by this procedure. We thus felt that the use of 1 and 2 in cycloadditions could be very useful for the preparation of a wide variety of fluorinated heterocyclic
* Corresponding author. Tel.: +1 618 650 3582. E-mail address: [email protected] (T.B. Patrick). 0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jfluchem.2013.05.004
Cyclization of 2 with the aryl N-methylnitrones (3) was accomplished in 61–70% yield by refluxing the components in toluene for 6–16 h followed by flash column chromatography to yield the fluoro-isoxazolidines (Table 1).
T.B. Patrick, A.H. Khan / Journal of Fluorine Chemistry 155 (2013) 59–61
60 Table 1 Yields and F NMR shifts for 4a–4f
3.2. 5-Fluoro-2-methyl-3-phenyl-isoxazolidine-4-carboxylic acid ethyl ester (4a) 1
H NMR (CDCl3, TMS) d 0.83 (t, 3H, J = 6.00 Hz, CH3), d 2.73 (s, 3H, N-CH3), d 3.76 (q, 1 H, C4), d 3.79 (q, 2H, J = 6 Hz, CH2), d 3.81 (d, 1 H, C3), d 5.89 (dd, 1 H, J1 = 63 Hz, J2 = 6 Hz, CHF), d 7.19–7.32 (m, 5H, C6H5); 13C NMR (CDCl3, TMS) d 13.86 (s, CH2CH3), d 44.4 (s, NCH3), d 58.8 (d, J1 = 23.40 Hz, C4), d 61.1 (s, CH2CH3), d 73.3 (s, C3), d 105.3 (d, C5, J1 = 240.8 Hz), d 126.1 (s, aromatic), d 128.4–128.6 (m, 4 C, C6H5), d 133.85 (s, 1 C, C6H5), d 165.7 (s, 1 C, CO); m/e 253.11. . Compound
% Yield
4a (H) 4b (OCH3) 4c (Cl) 4d (2-furyl) 4e (2-thienyl) 4f (CH3)
65 64 68 66 61 70
F NMF (CDCl3) 120.9 120.6 120.4 120.5 120.6 120.3
3.3. 5-Fluoro-3-(4-methoxyphenyl)-2-methyl-isoxazolidine-4carboxylic acid ethyl ester (4b) 1 H NMR (CDCl3, TMS) d 0.89 (t, 3H, J = 6.00 Hz, CH3), d 2.72 (s, 3H, N-CH3), d 3.72 (s, 3H, CH3O), d 3.85 (q, 1 H, C4), d 3.76 (q, 2H, J = 6 Hz, CH2), d 3.84 (d, 1H, C-3), d 5.86 (dd, 1 H, J1 = 63 Hz, J2 = 6 Hz, CHF), d 7.77 (d, 2H, J = 9, CH), 7.25 (d, 2H, J = 9, CH); 13C NMR (CDCl3, TMS) d 14.2 (s, CH2CH3), d 21.4 (s, CH3C6H4-), d 47.0 (s, N-CH3), d 61.7 (s, CH2CH3), d 62.1 (d, C4, J1 = 37.7 Hz), d 71.1 (s, C3), d 107.55 (d, C5, J = 240.1 Hz), d 127.38–127.83 (s, 4 C, 2,3,5,6-CC6H4-), d 133.41 (s, 1 C,-C6H4-), d 138.6 (s, 1 C, C6H4-), d 166.2 (s, 1 C, CO); m/e 283.12.
3.4. 3-(4-Chlorophenyl)-5-fluoro-2-methyl-isoxazolidine-4carboxylic acid ethyl ester (4c)
Fig. 1.
The regioselectivity of the reaction depicted in Fig. 1 shows the oxygen attacking the fluorine side of the alkene. Similar regioselectivity was found in reactions of fluoromaleates with nitrones [5]. The stereoselectivity of nitrone additions to alkenes is influenced by the stereochemistry of the substituents on the alkene [6–8]. In our reactions the [Z] stereochemistry of the alkene is maintained in the product fluoro-isoxazolidines. The stereoselectivity observed is described for compound 4f (R = CH3), where H3 is observed as a doublet from coupling with F5. At F5 (d-44) the F is coupled with H5 (J = 85 Hz), H4 (J = 20 Hz) and with H3 (J = 14 Hz). A NOESY spectrum of 4f shows enhancement between H4 and H5, but no enhancement with H3. Overall this methodology offers a facile entry into fluorinated isooxazolidinones.
1 H NMR (CDCl3, TMS) d 0.90 (t, 3H, J = 6.0 Hz, CH3), d 2.73 (s, 3H, N-CH3), d 3.77 (q, 2H, J = 6 Hz, CH2), d 3.80 (q, 1 H, C4), d 3.86 (d, 1 H, C3), d 5.89 (dd, 1 H, J1 = 63 Hz, J2 = 6 Hz, CHF), d 7.19–7.31 (m, 4 H, C6H4Cl); 13C NMR (CDCl3, TMS) d 13.94 (s, CH2CH3), d 44.4 (s, NCH3), d 58.3 (d, J1 = 24.91 Hz, C4), d 61.3 (s, CH2CH3), d 72.2 (s, C3), d 105.3 (d, C-5, J1 = 240.8 Hz), d 128.6 (s, 2 C, C6H4Cl), d 130.3 (s, 1 C, C6H4Cl), d 134.3 (s, 1C, C6H4Cl), d 152.4 (s, 1 C, C6H4Cl), d 165.4 (s, CO); m/e 287.07.
3.5. 5-Fluoro-3-(2-furyl)-2-methyl-isoxazolidine-4-carboxylic acid ethyl ester (4d) 1
H NMR (CDCl3, TMS) d 1.08 (t, 3H, J = 6.00 Hz, CH3), d 2.83 (s, 3H, N-CH3), d 3.39 (dd, 1 H, J = 6, C4), d 3.39 (q, 2H, J = 6 Hz, CH2), d 4.22 (d, H, J = 9 Hz, C3), d 5.89 (dd, 1 H, J1 = 63 Hz, J2 = 6 Hz, CHF), 6.88–7.23 (m, 3H, Furan); 13C NMR (CDCl3, TMS) d 14.12 (s, CH2CH3), d 45.11 (s, N-CH3), d 56.46 (d, J1 = 24.16 Hz, C-4), d 60.5 (s, CH2CH3), d 66.0 (s, C-3), d 105.5 (d, C-5, J1 = 240.1 Hz), d 109.7, 110.9, 111.12 (s, 3 C, Furan), d 142.6 (s, 1 C, Furan), d 165.5 (s, 1 C, CO); m/e 319.12. 3.6. 5-Fluoro-2-methyl-3-(2-thienyl)-isoxazolidine-4-carboxylic acid ethyl ester (4e)
3. Experimental procedure 3.1. General 1
H NMR data were recorded at 300.0 MHz with tetramethylsilane (d = 0.00 ppm) as internal reference. 13C NMR spectra were recorded at 75.5 MHz with deuterated chloroform (CDCl3 d 77.0 ppm) as internal reference. 19F NMR spectra were recorded at 282.3 MHz with trifluoroacetic acid (TFA d = 0.00 ppm) as external reference, and are corrected to CFCl3 (76.5 ppm upfield from TFA). Deuterated chloroform was the solvent in all cases. The fluorinated isoxazolidines (4a–4f) were synthesized by refluxing 1.50 mmol of ethyl (Z)-2-fluoropropenoate (2) with 1.50 mmol of nitrones (3a–3f) in toluene for 6–16 h. The compounds were purified by flash column chromatography with hexane/ethyl acetate as eluent solvents.
1 H NMR (CDCl3, TMS) d 1.00 (t, 3H, J = 6.00 Hz, CH3), d 2.75 (s, 3H, N-CH3), d 3.89 (q, 1 H, C-4), d 4.06 (q, 2H, J = 6 Hz, CH2), d 4.22 (d, 1 H, C3), d 5.89 (dd, 1 H, J1 = 63 Hz, J2 = 6 Hz, CHF), d 6.35 (dd, 2H, CH), 7.37 (s, 1H, CH); 13C NMR (CDCl3, TMS); d 44.05 (d, J1 = 84.7 Hz, CFH); d 12.77 (s, CH3CH2), d 43.41 (s, CH3N), d 57.02 (d, C-4), d 60.1 (s, CH3CH2), d 104.2 (d, C-5, J = 237.8 Hz), d 124. 95–126.29 (m, 3C, thiophene), d 135.7 (s, SC = CH), d 164.3 (s, C = O); m/e 335.10.
3.7. 5-Fluoro-2-methyl-3-p-tolyl-isoxazolidine-4-carboxylic acid ethyl ester (4f) 1 H NMR (CDCl3, TMS) d 0.86 (t, 3H, J = 6.00 Hz, CH3), d 2.24 (s, 3H, CH3C6H4), d 2.72 (s, 3H, N-CH3), d 3.89 (q, 1H, C4), d 3.78 (q, 2H, J = 6 Hz, CH2), d 3.83 (d, 1 H, C-3), d 5.87 (dd, 1 H, J1 = 63 Hz,
T.B. Patrick, A.H. Khan / Journal of Fluorine Chemistry 155 (2013) 59–61
J2 = 6 Hz, CHF), d 7.03 (d, 2H, J = 8.1, CH), 7.200 (d, 2H, J = 8.1, CH); 13 C NMR (CDCl3, TMS) d 12.59 (s, CH2CH3), d 20.05 (s, CH3 C6H4-), d 43.06 (s, N-CH3), d 57.35 (d, C4, J1 = 37.7 Hz), d 59.75 (s, CH2CH3), d 71.97 (s, C3), d 104.00 (d, C5, J1 = 241.1 Hz), d 127.4–127.8 (s, 2,3,5,6-C-C6H4-), d 130.4 (s, C6H4-), d 136.8 (s, C6H4-), d 164.5 (s, CO); m/e 267.13. 3.8. Nitrones (3a–3f) The nitrones were prepared by heating at reflux a mixture of Nmethylhydroxylamine and an aromatic aldehyde for 18 h. The nitrones were purified by flash chromatography. Some of these compounds have been reported previously by us [5]. N-methylphenylnitrone (3a): 1H NMR d 3.8 (CH3, 3H), 7.31 (m, 5H, aromatic) 8.09 (m, 1H, CH). N-methyl-4-methoxyphenylnitrone (3b): 1H NMR d 3.8 (s, CH3) 3.9 (s, CH3), 6.9–7.3 (m, 4H, aromatic), 8.1 (m, 1H, CH). N-methyl-4-chlorophenylnitrone (3c): 1 H NMR d 3.8 (s, 3H, CH3), 7.4–8.3 (m, 4H, aromatic), 7.08 (m, 1H, CH). N-methyl-2-furanylnitrone (3d): 1H NMR d 3.8 (s, 3H, CH3), 6.5, 7.4–7.7 (m, 3H, furan), 7.8 (m, 1H CH). N-methyl-2thienylnitrone (3e): 1H NMR d 3.81 (s, 3H NCH3), 7.05–7.41 (m,
61
3H, thiophene), 7.82 (s, 1H, CH). N-methyl-4-tolylnitrone (3f): 1H NMR d 2.25 (s, 3H, CH3), 3.81 (s, 3H, NCH3), 7.15 (d, 2H, aromatic), 8.05 (d, 2H, aromatic), 7.31 (s, 1H, CH) Acknowledgments This research was funded through a seed grant program (STEP) administered by Southern Illinois University at Edwardsville.
References [1] G. Haufe, in: V.A. Soloshonok (Ed.), Fluorine Containing Synthons, ACS Symposium Series 911, 2005 (Chapter 5). [2] B.F. Bonini, F. Boschi, M.C. Franchini, F. Fini, A. Ricci, Synlett 4 (2006) 543. [3] A.A. Gakh, K.L. Kirk, J. Amer. Chem. Soc. (2009). [4] T.B. Patrick, J. Neuman, A. Tatro, J. Fluorine Chem. 132 (2011) 779. [5] T.B. Patrick, M. Shadmehr, A. Kang, R. Singh, B. Asmelash, J. Fluorine Chem. 143 (2012) 109. [6] R. Huisgen, Angew. Chem. Int. Ed. 2 (1963) 565. [7] K.V. Gothell, K.A. Jorgensen, Chem. Rev. 98 (1998) 863. [8] R.C.F. Jones, J.N. Martin, A. Padwa, in: W.H. Pearson (Ed.), Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products, Wiley, New York, NY, 2002, pp. 1–81.
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry journal homepage: www.elsevier.com/locate/fluor
[3 + 2] Cycloaddition reactions of ethyl (Z)-3-fluoropropenoate with nitrones Timothy B. Patrick *, Akbar H. Khan Department of Chemistry, Southern Illinois University, Edwardsville, IL, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 5 March 2013 Received in revised form 26 April 2013 Accepted 8 May 2013 Available online 27 May 2013
Ethyl (Z)-2-fluoropropenoate reacts stereospecifically and regioselectively in [3 + 2] cycloadditions with aryl N-methylnitrones. The yields of the cycloaddition products range from 61 to 70%. ß 2013 Elsevier B.V. All rights reserved.
Keywords: Ethyl (Z)-2-fluoropropenoate Fluoro-isoxazolidines Aryl N-methylnitrone [3 + 2] Cycloadditions
1. Introduction Cycloaddition reactions of fluorinated alkenes represent an important new methodology for the preparation of fluorinated carbocycles [1,2] and fluorinated heterocycles. [3]. Following our studies of Diels–Alder cycloadditons and [3 + 2] cycloadditions of diethyl (E)-fluoromaleates (1) [4,5], we now extend our research to include [3 + 2] cycloadditions of ethyl (Z)fluoropentenoate (2) [5]. Although Huisgen’s methodology is long known [6], very little is reported on the preparation of ringfluorinated heterocycles by [3 + 2] cyclizations [2].
compounds with applications in biological sciences. We have already reported that cycloadditions with 1 and nitrones occurs readily in a concerted manner [5]. This paper describes our reactions between 2 and nitrones and an NMR study of the reaction stereochemistry. 2. Results and discussion Both the preparation of 2 [4] and the aromatic nitrones 3a, 3b, 3c, 3d, 3e and 3f have been described by us previously [5].
The concept of [3 + 2] cycloaddition reactions was reviewed in 1963 by Huisgen [6]. Many new materials with widespread biological use have been prepared by this procedure. We thus felt that the use of 1 and 2 in cycloadditions could be very useful for the preparation of a wide variety of fluorinated heterocyclic
* Corresponding author. Tel.: +1 618 650 3582. E-mail address: [email protected] (T.B. Patrick). 0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jfluchem.2013.05.004
Cyclization of 2 with the aryl N-methylnitrones (3) was accomplished in 61–70% yield by refluxing the components in toluene for 6–16 h followed by flash column chromatography to yield the fluoro-isoxazolidines (Table 1).
T.B. Patrick, A.H. Khan / Journal of Fluorine Chemistry 155 (2013) 59–61
60 Table 1 Yields and F NMR shifts for 4a–4f
3.2. 5-Fluoro-2-methyl-3-phenyl-isoxazolidine-4-carboxylic acid ethyl ester (4a) 1
H NMR (CDCl3, TMS) d 0.83 (t, 3H, J = 6.00 Hz, CH3), d 2.73 (s, 3H, N-CH3), d 3.76 (q, 1 H, C4), d 3.79 (q, 2H, J = 6 Hz, CH2), d 3.81 (d, 1 H, C3), d 5.89 (dd, 1 H, J1 = 63 Hz, J2 = 6 Hz, CHF), d 7.19–7.32 (m, 5H, C6H5); 13C NMR (CDCl3, TMS) d 13.86 (s, CH2CH3), d 44.4 (s, NCH3), d 58.8 (d, J1 = 23.40 Hz, C4), d 61.1 (s, CH2CH3), d 73.3 (s, C3), d 105.3 (d, C5, J1 = 240.8 Hz), d 126.1 (s, aromatic), d 128.4–128.6 (m, 4 C, C6H5), d 133.85 (s, 1 C, C6H5), d 165.7 (s, 1 C, CO); m/e 253.11. . Compound
% Yield
4a (H) 4b (OCH3) 4c (Cl) 4d (2-furyl) 4e (2-thienyl) 4f (CH3)
65 64 68 66 61 70
F NMF (CDCl3) 120.9 120.6 120.4 120.5 120.6 120.3
3.3. 5-Fluoro-3-(4-methoxyphenyl)-2-methyl-isoxazolidine-4carboxylic acid ethyl ester (4b) 1 H NMR (CDCl3, TMS) d 0.89 (t, 3H, J = 6.00 Hz, CH3), d 2.72 (s, 3H, N-CH3), d 3.72 (s, 3H, CH3O), d 3.85 (q, 1 H, C4), d 3.76 (q, 2H, J = 6 Hz, CH2), d 3.84 (d, 1H, C-3), d 5.86 (dd, 1 H, J1 = 63 Hz, J2 = 6 Hz, CHF), d 7.77 (d, 2H, J = 9, CH), 7.25 (d, 2H, J = 9, CH); 13C NMR (CDCl3, TMS) d 14.2 (s, CH2CH3), d 21.4 (s, CH3C6H4-), d 47.0 (s, N-CH3), d 61.7 (s, CH2CH3), d 62.1 (d, C4, J1 = 37.7 Hz), d 71.1 (s, C3), d 107.55 (d, C5, J = 240.1 Hz), d 127.38–127.83 (s, 4 C, 2,3,5,6-CC6H4-), d 133.41 (s, 1 C,-C6H4-), d 138.6 (s, 1 C, C6H4-), d 166.2 (s, 1 C, CO); m/e 283.12.
3.4. 3-(4-Chlorophenyl)-5-fluoro-2-methyl-isoxazolidine-4carboxylic acid ethyl ester (4c)
Fig. 1.
The regioselectivity of the reaction depicted in Fig. 1 shows the oxygen attacking the fluorine side of the alkene. Similar regioselectivity was found in reactions of fluoromaleates with nitrones [5]. The stereoselectivity of nitrone additions to alkenes is influenced by the stereochemistry of the substituents on the alkene [6–8]. In our reactions the [Z] stereochemistry of the alkene is maintained in the product fluoro-isoxazolidines. The stereoselectivity observed is described for compound 4f (R = CH3), where H3 is observed as a doublet from coupling with F5. At F5 (d-44) the F is coupled with H5 (J = 85 Hz), H4 (J = 20 Hz) and with H3 (J = 14 Hz). A NOESY spectrum of 4f shows enhancement between H4 and H5, but no enhancement with H3. Overall this methodology offers a facile entry into fluorinated isooxazolidinones.
1 H NMR (CDCl3, TMS) d 0.90 (t, 3H, J = 6.0 Hz, CH3), d 2.73 (s, 3H, N-CH3), d 3.77 (q, 2H, J = 6 Hz, CH2), d 3.80 (q, 1 H, C4), d 3.86 (d, 1 H, C3), d 5.89 (dd, 1 H, J1 = 63 Hz, J2 = 6 Hz, CHF), d 7.19–7.31 (m, 4 H, C6H4Cl); 13C NMR (CDCl3, TMS) d 13.94 (s, CH2CH3), d 44.4 (s, NCH3), d 58.3 (d, J1 = 24.91 Hz, C4), d 61.3 (s, CH2CH3), d 72.2 (s, C3), d 105.3 (d, C-5, J1 = 240.8 Hz), d 128.6 (s, 2 C, C6H4Cl), d 130.3 (s, 1 C, C6H4Cl), d 134.3 (s, 1C, C6H4Cl), d 152.4 (s, 1 C, C6H4Cl), d 165.4 (s, CO); m/e 287.07.
3.5. 5-Fluoro-3-(2-furyl)-2-methyl-isoxazolidine-4-carboxylic acid ethyl ester (4d) 1
H NMR (CDCl3, TMS) d 1.08 (t, 3H, J = 6.00 Hz, CH3), d 2.83 (s, 3H, N-CH3), d 3.39 (dd, 1 H, J = 6, C4), d 3.39 (q, 2H, J = 6 Hz, CH2), d 4.22 (d, H, J = 9 Hz, C3), d 5.89 (dd, 1 H, J1 = 63 Hz, J2 = 6 Hz, CHF), 6.88–7.23 (m, 3H, Furan); 13C NMR (CDCl3, TMS) d 14.12 (s, CH2CH3), d 45.11 (s, N-CH3), d 56.46 (d, J1 = 24.16 Hz, C-4), d 60.5 (s, CH2CH3), d 66.0 (s, C-3), d 105.5 (d, C-5, J1 = 240.1 Hz), d 109.7, 110.9, 111.12 (s, 3 C, Furan), d 142.6 (s, 1 C, Furan), d 165.5 (s, 1 C, CO); m/e 319.12. 3.6. 5-Fluoro-2-methyl-3-(2-thienyl)-isoxazolidine-4-carboxylic acid ethyl ester (4e)
3. Experimental procedure 3.1. General 1
H NMR data were recorded at 300.0 MHz with tetramethylsilane (d = 0.00 ppm) as internal reference. 13C NMR spectra were recorded at 75.5 MHz with deuterated chloroform (CDCl3 d 77.0 ppm) as internal reference. 19F NMR spectra were recorded at 282.3 MHz with trifluoroacetic acid (TFA d = 0.00 ppm) as external reference, and are corrected to CFCl3 (76.5 ppm upfield from TFA). Deuterated chloroform was the solvent in all cases. The fluorinated isoxazolidines (4a–4f) were synthesized by refluxing 1.50 mmol of ethyl (Z)-2-fluoropropenoate (2) with 1.50 mmol of nitrones (3a–3f) in toluene for 6–16 h. The compounds were purified by flash column chromatography with hexane/ethyl acetate as eluent solvents.
1 H NMR (CDCl3, TMS) d 1.00 (t, 3H, J = 6.00 Hz, CH3), d 2.75 (s, 3H, N-CH3), d 3.89 (q, 1 H, C-4), d 4.06 (q, 2H, J = 6 Hz, CH2), d 4.22 (d, 1 H, C3), d 5.89 (dd, 1 H, J1 = 63 Hz, J2 = 6 Hz, CHF), d 6.35 (dd, 2H, CH), 7.37 (s, 1H, CH); 13C NMR (CDCl3, TMS); d 44.05 (d, J1 = 84.7 Hz, CFH); d 12.77 (s, CH3CH2), d 43.41 (s, CH3N), d 57.02 (d, C-4), d 60.1 (s, CH3CH2), d 104.2 (d, C-5, J = 237.8 Hz), d 124. 95–126.29 (m, 3C, thiophene), d 135.7 (s, SC = CH), d 164.3 (s, C = O); m/e 335.10.
3.7. 5-Fluoro-2-methyl-3-p-tolyl-isoxazolidine-4-carboxylic acid ethyl ester (4f) 1 H NMR (CDCl3, TMS) d 0.86 (t, 3H, J = 6.00 Hz, CH3), d 2.24 (s, 3H, CH3C6H4), d 2.72 (s, 3H, N-CH3), d 3.89 (q, 1H, C4), d 3.78 (q, 2H, J = 6 Hz, CH2), d 3.83 (d, 1 H, C-3), d 5.87 (dd, 1 H, J1 = 63 Hz,
T.B. Patrick, A.H. Khan / Journal of Fluorine Chemistry 155 (2013) 59–61
J2 = 6 Hz, CHF), d 7.03 (d, 2H, J = 8.1, CH), 7.200 (d, 2H, J = 8.1, CH); 13 C NMR (CDCl3, TMS) d 12.59 (s, CH2CH3), d 20.05 (s, CH3 C6H4-), d 43.06 (s, N-CH3), d 57.35 (d, C4, J1 = 37.7 Hz), d 59.75 (s, CH2CH3), d 71.97 (s, C3), d 104.00 (d, C5, J1 = 241.1 Hz), d 127.4–127.8 (s, 2,3,5,6-C-C6H4-), d 130.4 (s, C6H4-), d 136.8 (s, C6H4-), d 164.5 (s, CO); m/e 267.13. 3.8. Nitrones (3a–3f) The nitrones were prepared by heating at reflux a mixture of Nmethylhydroxylamine and an aromatic aldehyde for 18 h. The nitrones were purified by flash chromatography. Some of these compounds have been reported previously by us [5]. N-methylphenylnitrone (3a): 1H NMR d 3.8 (CH3, 3H), 7.31 (m, 5H, aromatic) 8.09 (m, 1H, CH). N-methyl-4-methoxyphenylnitrone (3b): 1H NMR d 3.8 (s, CH3) 3.9 (s, CH3), 6.9–7.3 (m, 4H, aromatic), 8.1 (m, 1H, CH). N-methyl-4-chlorophenylnitrone (3c): 1 H NMR d 3.8 (s, 3H, CH3), 7.4–8.3 (m, 4H, aromatic), 7.08 (m, 1H, CH). N-methyl-2-furanylnitrone (3d): 1H NMR d 3.8 (s, 3H, CH3), 6.5, 7.4–7.7 (m, 3H, furan), 7.8 (m, 1H CH). N-methyl-2thienylnitrone (3e): 1H NMR d 3.81 (s, 3H NCH3), 7.05–7.41 (m,
61
3H, thiophene), 7.82 (s, 1H, CH). N-methyl-4-tolylnitrone (3f): 1H NMR d 2.25 (s, 3H, CH3), 3.81 (s, 3H, NCH3), 7.15 (d, 2H, aromatic), 8.05 (d, 2H, aromatic), 7.31 (s, 1H, CH) Acknowledgments This research was funded through a seed grant program (STEP) administered by Southern Illinois University at Edwardsville.
References [1] G. Haufe, in: V.A. Soloshonok (Ed.), Fluorine Containing Synthons, ACS Symposium Series 911, 2005 (Chapter 5). [2] B.F. Bonini, F. Boschi, M.C. Franchini, F. Fini, A. Ricci, Synlett 4 (2006) 543. [3] A.A. Gakh, K.L. Kirk, J. Amer. Chem. Soc. (2009). [4] T.B. Patrick, J. Neuman, A. Tatro, J. Fluorine Chem. 132 (2011) 779. [5] T.B. Patrick, M. Shadmehr, A. Kang, R. Singh, B. Asmelash, J. Fluorine Chem. 143 (2012) 109. [6] R. Huisgen, Angew. Chem. Int. Ed. 2 (1963) 565. [7] K.V. Gothell, K.A. Jorgensen, Chem. Rev. 98 (1998) 863. [8] R.C.F. Jones, J.N. Martin, A. Padwa, in: W.H. Pearson (Ed.), Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products, Wiley, New York, NY, 2002, pp. 1–81.