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Synlett 2008(16): 2503-2507  
DOI: 10.1055/s-2008-1078179
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Rapid Access to New Fluorinated 1,3-Dienes and Benzylic Fluorides via Metathesis on Propargylic Fluorides

Sandip A. Pujaria, Krishna P. Kaliappan*a, Alain Valleixb, Danielle Gréec, René Grée*c
a Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
Fax: +91(22)25723480; e-Mail: kpk@chem.iitb.ac.in;
b Euriso-top, Centre d’Etudes Nucléaires de Saclay, 91191 Gif sur Yvette, France
c Chimie et Photonique Moléculaires,CNRS UMR 6510, Université de Rennes 1, Avenue du Général Leclerc, 35042 Rennes Cedex, France
e-Mail: rene.gree@univ-rennes1.fr;
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Publication History

Received 1 June 2008
Publication Date:
10 September 2008 (online)

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Abstract

The cross enyne metathesis reaction of propargylic fluoride (+)-12 with ethylene affords the enantioenriched 1,3-diene (+)-14 having fluorine-containing side chain at 2-position in good yield. Upon Diels-Alder reaction, followed by aromatization, this diene affords the new benzylic fluorides (+)-16 and (+)-17 in high ee values. This new strategy has been successfully extended to the corresponding gem-difluoro diene 21 and benzylic fluorides 23 and 24.

Key words

dehydroxyfluorination - enyne metathesis - Diels-Alder reaction - aromatization - benzylic fluorides

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19

All our attempts to measure the ee values of the intermediates (+)-14 and (+)-15 by NMR in the presence of chiral shift reagents or by chiral HPLC have been unsuccessful so far. This is a well known problem for such chiral monofluorinated molecules, see for instance ref 16a.

20

General Procedure for Cross Enyne Metathesis: A solution of propargyl fluoride (1 mmol) in degassed CH2Cl2 (10 mL) was purged with ethylene and treated with the Grubbs II catalyst 13 (5 or 10 mol%). The reaction mixture was refluxed for 15 h under ethylene atmosphere. After being cooled to r.t., the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to afford the fluorodiene. Spectral data for diene (+)-14: R f 0.71 (pentane); [α]D ²0 8.0 (c = 0.2, CHCl3). IR (neat): 2927, 1966, 1650, 1456, 1216, 1023, 759 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 6.28-6.38 (m, 1 H, H2), 5.05-5.31 (m, 5 H, 2 × =CH2, CHF), 1.28-1.52 (m, 14 H, 7 × CH2), 1.72-1.83 (m, 2 H, CH2), 0.90 (t, J = 6.6 Hz, 3 H, Me). ¹³C NMR (75 MHz, CDCl3): δ = 145.1 (d, J = 17.5 Hz, C3), 135.3 (d, J = 3.9 Hz, C2), 115.0 (d, J = 10.5 Hz, C14), 114.7 (C1), 92.1 (d, J = 171.5 Hz, C4), 34.7 (d, J = 22.6 Hz, CH2CHF), 31.9, 29.5, 29.4, 29.3, 25.1(d, J = 3.5 Hz), 22.7 (6 × d, J = 3.5 Hz, 6 × CH2), 14.1 (Me). ¹9F NMR (282 MHz, CDCl3): δ = -181.9 (dt, J H-F = 48.7, 23.6 Hz). HRMS: m/z [M]+ calcd for C14H25F: 212.1940; found: 212.1933. Spectral data for diene 21: R f 0.91 (pentane). IR (neat): 2955, 2927, 2855, 1682, 1596, 1467, 1174, 1087, 1004 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 6.27 (dd, J = 17.7, 11.3 Hz, 1 H, H2), 5.53 (dd, J = 17.7, 1.3 Hz, 1 H, H1), 5.44 (d, J = 5.5 Hz, 2 H, H14), 5.23 (d, J = 11.3 Hz, 1 H, H1), 1.91-2.07 (m, 2 H, CH2), 1.22-1.45 (m, 14 H, 7 × CH2), 0.91 (t, J = 6.8 Hz, 3 H, Me). ¹³C NMR (75 MHz, CDCl3): δ = 142.5 (t, J = 24.2 Hz, C3), 132.6 (t, J = 2.8 Hz, C2), 122.4 (t, J = 242.4 Hz, C4), 117.3 (t, J = 1.4 Hz, C1), 116.3 (t, J = 9.5 Hz, C14), 36.5 (t, J = 26.1 Hz, CH2CF2), 31.8, 29.4, 29.3, 29.27, 29.23, 22.6, 22.3 (t, J = 4.3 Hz), 14.1 (Me). ¹9F NMR (282 MHz, CDCl3): δ = -97.44 (t, J H-F = 16.6 Hz). HRMS: m/z [M]+ calcd for C14H24F2: 230.1846; found: 230.1846.

21

General Procedure for Diels-Alder Reaction with Diethyl Acetylenedicarboxylate Followed by Aromatization: A mixture of diene (1 mmol) and diethyl acetylenedicarboxylate (1.2 mmol) was heated at 60 ˚C in an oil bath for 3 h. After bringing the mixture to r.t., the crude material was purified by silica gel column chromatography to give the cycloadduct. To a solution of the above cycloadduct (1 mmol) in CH2Cl2 (40 mL) was added MnO2 (10 mmol) and the mixture was refluxed for 2 d. After being cooled to r.t., the reaction mixture was passed through a small pad of celite and the filtrate was concentrated and purified by flash column chromatography on silica gel to afford the corresponding aromatized product.

22

General Procedure for One-Pot Diels-Alder Reaction with 1,4-Naphthaquinone and Aromatization: A solution of diene (1 mmol) in anhyd toluene (15 mL) was treated with 1,4-naphthaquinone (1.2 mmol) and the resulting mixture was heated at 70 ˚C for 2 d. The solvent was removed and the crude product was dissolved in CHCl3 (4 mL). To this solution silica gel purged in Et3N (2 g) was added and the mixture was stirred for another 3 h at r.t. The reaction mixture was concentrated and the crude material was purified by column chromatography to afford the corresponding aromatized adducts.

23

Spectral data for selected compounds: Compound (+)-16: R f 0.30 (pentane-Et2O, 9:1); [α]D ²0 14.8 (c = 0.2, CHCl3). IR (neat): 3020, 1966, 1731, 1650, 1216, 1045, 758 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 7.75 (d, J = 8.0 Hz, 1 H, H6), 7.65 (s, 1 H, H3), 7.49 (dd, J = 8.0, 1.6 Hz, 1 H, H5), 5.55 (ddd, J = 47.7, 8.0, 4.7 Hz, 1 H, CHF), 4.35-4.43 (m, 4 H, 2 × CH2), 1.87-1.91 (m, 2 H, CH2), 1.19-1.44 (m, 20 H, 7 × CH2, 2 × Me), 0.89 (t, J = 6.4 Hz, 3 H, Me). ¹³C NMR (75 MHz, CDCl3): δ = 167.5 (COOCH2), 167.2 (COOCH2), 144.1 (d, J = 20.6 Hz, C4), 132.6, 131.6 (d, J = 1.4 Hz), 129.2, 127.6 (d, J = 7.4 Hz, CAr), 125.7 (d, J = 7.6 Hz, CAr), 92.9 (d, J = 173.2 Hz, CHF), 61.7 (OEt), 61.6 (OEt), 37.2 (d, J = 22.9 Hz, CH2CHF), 31.8, 29.5, 29.4, 29.3, 29.2, 24.8 (d, J = 3.9 Hz), 22.7 (7 × d, J = 3.9 Hz, 7 × CH2), 14.2, 14.1 (2 × Me). ¹9F NMR (282 MHz, CDCl3): δ = -178.9 (ddd, J H-F = 47.5, 28.9, 18.8 Hz). HRMS: m/z [M]+ calcd for C22H33O4F: 380.2362; found: 380.2381. Compound 17: R f 0.28 (pentane-Et2O, 7:3); mp 65-67 ˚C; [α]D ²0 3.0 (c = 0.2, CHCl3). IR (KBr): 3430, 3019, 1653, 1215, 1045 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 7.27-7.38 (m, 3 H, HAr), 5.43 (ddd, J = 47.8, 8.0, 4.9 Hz, 1 H, CHF), 4.74 (s, 2 H, CH2OH), 4.73 (s, 2 H, CH2OH), 3.67 (br s, 2 H, OH), 1.37-1.97 (m, 2 H, CH2), 1.09-1.22 (m, 14 H, 7 × CH2), 0.89 (t, J = 6.9 Hz, 3 H, Me). ¹³C NMR (75 MHz, CDCl3): δ = 140.9 (d, J = 19.9 Hz, C4), 139.6, 139.2 (d, J = 2.0 Hz), 129.7, 126.7 (d, J = 6.6 Hz, CAr), 125.5 (d, J = 6.8 Hz, CAr), 94.4 (d, J = 170.3 Hz, CHF), 63.8 (CH2OH), 63.6 (CH2OH), 37.2 (d, J = 23.4 Hz, CH2CHF), 31.8, 29.5, 29.4, 29.3, 29.2, 25.1, 22.7 (d, J = 4.2 Hz), 14.1 (Me). ¹9F NMR (282 MHz, CDCl3): δ = -174.64 (ddd, J H-F = 46.7, 29.6, 17.9 Hz). HRMS: m/z [M - F]+ calcd for C18H29O2: 277.2167; found: 277.2178. Chiral HPLC analysis: column Chiralpack AD, eluent: hexane-EtOH, 98:2; flow rate: 1 mL/min; UV detection at λ = 225 nm; t R(17) = 16.8 min; t R (ent-17) = 19 min. Compound 18: R f 0.70 (pentane-Et2O, 9:1); mp 99-101 ˚C. IR (KBr): 2919, 2849, 1676, 1593, 1351, 1290, 1156, 1021 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 8.30-8.35 (m, 2 H, HAr), 8.24 (s, 1 H, HAr), 7.28-7.85 (m, 4 H, HAr), 5.62 (ddd, J = 47.7, 7.9, 4.8 Hz, 1 H, CHF), 1.89-2.02 (m, 2 H, CH2), 1.22-1.52 (m, 14 H, 7 × CH2), 0.88 (t, J = 7.0 Hz, 3 H, Me). ¹³C NMR (75 MHz, CDCl3): δ = 182.9 (COOCH2), 182.7 (COOCH2), 147.3 (d, J = 20.5 Hz, CAr), 134.2, 134.1, 133.6, 133.5, 133.1 (d, J = 1.4 Hz), 130.7 (d, J = 7.6 Hz, CAr), 127.7, 127.3, 127.2, 124.0 (4 × d, J = 7.5 Hz, CAr), 92.6 (d, J = 173.9 Hz, CHF), 37.2 (d, J = 22.7 Hz, CH2CHF), 31.8, 29.5, 29.4, 29.3, 29.2, 24.8, 22.6 (d, J = 3.9 Hz), 14.1 (Me). ¹9F NMR (282 MHz, CDCl3): δ = -179.9 (ddd, J H-F = 47.7, 28.7, 19.1 Hz). HRMS: m/z [M]+ calcd for C24H27O2F: 366.1995; found: 366.1999. Compound 23: R f 0.34 (pentane-Et2O, 9:1). IR (neat): 2956, 2928, 2856, 1731, 1615, 1466, 1287, 1131, 1070, 775 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 7.83 (d, J = 1.2 Hz, 1 H, H3), 7.75 (d, J = 8.0 Hz, 1 H, H6), 7.63 (dd, J = 8.0, 1.2 Hz, 1 H, H5), 4.39 (q, J = 7.1 Hz, 2 H, OEt), 4.38 (q, J = 7.1 Hz, 2 H, OEt), 2.01-2.19 (m, 2 H, CH2), 1.25-1.41 (m, 20 H, 7 × CH2, 2 × Me), 0.87 (t, J = 6.4 Hz, 3 H, Me). ¹³C NMR (75 MHz, CDCl3): δ = 167.1 (COOCH2), 166.8 (COOCH2), 140.3 (t, J = 27.8 Hz, C4), 133.5 (t, J = 1.3 Hz), 132.3, 129.1, 127.6 (t, J = 6.1 Hz), 125.7 (t, J = 6.3 Hz, CAr), 122.3 (t, J = 243.0 Hz, CF2), 61.9 (OEt), 61.8 (OEt), 38.9 (t, J = 26.7 Hz, CH2CF2), 31.8, 29.4, 29.3, 29.2, 29.1, 22.6, 22.3 (t, J = 4.0 Hz), 14.1 (3 × Me). ¹9F NMR (282 MHz, CDCl3): δ = -96.25 (t, J H-F = 16.4 Hz). HRMS: m/z [M]+ calcd for C22H32O4F2: 398.2268; found: 398.2261. Compound 24: R f 0.71 (pentane-Et2O, 9:1); mp 88-90 ˚C. IR (KBr): 2920, 2851, 1673, 1594, 1340, 1163, 1129, 1031, 707 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 8.31-8.41 (m, 4 H, HAr), 7.80-7.91 (m, 3 H, HAr), 2.11-2.27 (m, 2 H, CH2), 1.25-1.50 (m, 14 H, 7 × CH2), 0.86 (t, J = 6.4 Hz, 3 H, Me). ¹³C NMR (75 MHz, CDCl3): δ = 182.5 (2 × COOCH2), 143.3 (t, J = 27.6 Hz, CAr), 134.3, 134.1 (t, J = 1.3 Hz), 130.5 (t, J = 6.0 Hz), 127.7, 127.4, 127.3, 124.1 (t, J = 6.1 Hz), 122.3 (t, J = 243.3 Hz, CF2), 38.8 (t, J = 26.6 Hz, CH2CF2), 31.8, 29.4, 29.3, 29.2, 29.1, 22.3 (t, J = 3.9 Hz), 14.1 (Me). ¹9F NMR (282 MHz, CDCl3): δ = -96.46 (t, J H-F = 16.4 Hz). HRMS: m/z [M]+ calcd for C24H26O2F2: 384.1900; found: 384.1915.