Practical Iron-Catalyzed Dehalogenation of Aryl Halides

Transcription

1 Practical Iron-Catalyzed Dehalogenation of Aryl alides Waldemar Maximilian Czaplik, Sabine Gruppe, Matthias Mayer and Axel Jacobi von Wangelin* Department of Chemistry, University of Cologne Greinstr. 4, Köln, Germany Fax: (+) 49 (0) omepage:

2 General. Analytical thin-layer chromatography. TLC was performed using aluminium plates with silica gel and fluorescent indicator (Merck, 60F 254 ). Thin layer chromatography plates were visualized by exposure to ultraviolet light and/or by immersion in a staining solution of molybdatophosphoric acid in ethanol. Column chromatography. Flash column chromatography with silica gel from KMF 60 ( mm). As solvents mixtures of cyclohexane and ethylacetate were used. Gaschromatography with mass selective detector. Agilent 6890N Network GC-System, Mass detector 5975 MS; Column: P-5MS (30m x 0.25 mm x 0.25, 5% phenylmethylsiloxane, from Macherey-Nagel); Carrier gas: hydrogen; Standard heating procedure: 50 C (2 min), 25 C/min -> 300 C (5 min). Gaschromatography with FID. P6890 GC-System with injector 7683B, carrier gas: hydrogen; GC-FID was used for reaction control, amine screening, catalyst screening and temperature screening (Calibration with internal standard pentadecane or dodecane and analytical pure samples). NMR. Proton and carbon nuclear magnetic resonance were recorded with uker DPX300 (300Mz). IR spectroscopy. ATR technique (Thermo Nicolet 380 FT-IR). Intensity: s = strong, m = medium und w = weak. igh resolution mass spectrometry (RMS). Mass spectra were taken at Finnigan MAT 900s (EI). Trisacetylacetonato-iron(III) from Acros Organics (99+%, anhydrous, pure) was stored in a Glovebox (Maun % N 2 ). TF was dried over sodium with benzophenone as indicator (reflux, freshly destilled)

3 Initial screening: Ethylmagnesium chloride. cat. Fe(acac) 3 Et-MgCl TF, 0 C, 1 h Scheme S1: Fe-catalyzed hydrodehalogenation with EtMgCl. + Table S1: Initial screening with EtMgCl and catalytic Fe(acac) 3. Fe(acac) 3 [mol%] Et-MgCl GC yield of 2 [%] GC yield of 3 [%] 10 5 equiv equiv equiv equiv equiv equiv equiv equiv equiv. 0 0 tert-butylmagnesium chloride. 1 mol% Fe(acac) 3 t-bu-mgcl TF, 0 C, 45 min 1 2 Scheme S2: Fe-catalyzed hydrodehalogenation with t-bumgcl. Figure S1: Yield of 2 in dependence on the amount of t-bumgcl.

4 General procedure (with tert-bumgcl). A 10 ml Schlenk tube was charged with Fe(acac) 3 (1-5 mol%), sealed with a rubber septum and purged with argon for 10 min. Dry TF (4 ml) was added, and the solution stirred at 0 C. tert-butylmagnesium chloride (1.7 M in TF; mmol) was added with a syringe. After 2 min, the arylhalide (1 mmol) was added. After 90 min, the reaction was quenched with saturated aqueous N 4 Cl (2 ml), extracted with ethyl acetate (3 x 4 ml). The organic phases were dried (Na 2 SO 4 ) and subjected to quantitative GC-FID (internal reference n-pentadecane) or silica gel flash column chromatography. For detailed reaction parameters, see Tables 1-3 in manuscript. Analytical data matched with a commercial sample or literature data. For (1R,2S,5R)-2-(pyridin-2-yl)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol (entry 4, table 3 in manuscript), see: S. Goto, J. Velder, S. El Sheikh, Y. Sakamoto, M. Mitani, S. Elmas, A. Adler, A. Becker, J.-M. Neudörfl, J. Lex,.-G. Schmalz, Synlett 2008, For 4-deuterobiphenyl, see: Y. Miura,. Oka, E. Yamano, M. Morita, J. Org. Chem. 1997, 62, ydrodehalogenation vs. Grignard formation. See Figure 1 in manuscript. ydrodehalogenation: See standard conditions for 4-bromobiphenyl (3 mmol scale, 0 C). Grignard formation: A 10 ml flask was charged with magnesium turnings (88.2 mg, 3.6 mmol) and purged with argon (1 min). TF (12 ml) was added, and the reaction cooled to 0 C. 4-omobiphenyl (3 mmol) was added dropwise with a syringe. Over a period of 2h, samples (50 μl) were taken, filtered through SiO 2 and analyzed by quantitative GC-FID (internal reference n-pentadecane). Deuteration experiments. D 2 O 1 mol% Fe(acac) equiv. t-bumgcl TF, 0 C, 90 min rt, 0.5 h no D incorporation! PhCO + rt, 0.5 h Scheme S3: Work-up with deuterium oxide (top) and benzaldehyde (bottom). 0% O Ph

5 Analysis of the crude reaction by 1 -,,-COSY, and 2 -NMR revealed the exclusive formation of biphenyl with no detectable deuterium incorporation. This documents that a metathesis reaction (magnesium exchange between aryl bromide and t-butylmagnesium chloride to give a 4-biphenyl Grignard species) is not operative. Similar results have been obtained when adding benzaldehyde to the crude reaction, as no benzyl alcohol products were detected. When using deuterated TF-d 8 as solvent and commercial t-butylmgcl as a 1.7 M solution in TF, the overall deuterium content of the solvent is 78%. With this solvent system, no incorporation of deuterium into the reduction product was observed ( 1 -,,-COSY, and 2 - NMR). 1 mol% Fe(acac) equiv. t-bumgcl TF-d 8, 0 C, 90 min Scheme S4: Use of TF-d 8 as solvent. no D incorporation! Preparation of C 2 D 5 Mg: A 10 ml test tube was charged with magnesium turnings (317 mg, 1.5 equiv., 13.2 mmol) and LiCl (444 mg, 1.2 equiv., 11 mmol) in an argon atmosphere and sealed with a rubber septum. Dry TF (5 ml) and DiBAl- (88 µl, 1 M in hexane, mmol) were added via syringe, and the reaction cooled to 0 C. After 5 min, bromoethane-d 5 (706 µl, 8.8 mmol) was added, and the reaction stirred for 2 h at 0 C. Subsequent reaction with 4-bromobiphenyl under the standard conditions gave 4-deuterobiphenyl with 100% deuterium incorporation ( 1 -, 2 - NMR). Two reaction runs with deuterated ethylmagnesium bromide (C 2 D 5 Mg) afforded exclusively 4-deuterobiphenyl (Scheme S5). 0.5 equiv. D D D D D 1.5 equiv. Mg 1.2 equiv. LiCl 0.01 mol% DiBAl TF, 0 C, 2 h D D D D D Mg Ph 5 mol% Fe(acac) 3 TF, 0 C, 90 min Ph D Scheme S5: Preparation of deuterated Ethyl-Mg and deuterodehalogenation of % D incorporation!

6 Alternative reductants. Grignard species without ß-hydrogen atoms: 1 mol% Fe(acac) equiv. MeMgCl TF, 0 C, 90 min Scheme S6: Use of MeMgCl as reductant. traces An identical result was obtained when employing 1.5 equiv. PhMgCl in TF as stoichiometric reductant. Pressurized 2 : A 5 ml tube was charged with Fe(acac) 3 (10 mol%) and 4-bromobiphenyl (0.5 mmol, 167 mg), sealed with a septum, and purged with argon for 10 min. Dry TF (2 ml) and TMEDA (80 mol%) were added, and the mixture cooled to 0 C. Then, ethylmagnesium chloride (50 mol%, 1.5 M in TF) was added, the vial transferred to a 100mL Parr highpressure reactor, and pressurized with hydrogen gas (50 bar). After 4 h at room temperature, the pressure was released. The reaction was quenched with saturated aqueous N 4 Cl (2 ml), extracted with ethyl acetate (3 x 4 ml), and analyzed by quantitative GC-FID to document the formation biphenyl with 18% yield. 10 mol% Fe(acac) 3 50 mol% EtMgCl 80 mol% TMEDA TF, rt, 50 bar 2 18% Scheme S7: Iron-catalyzed hydrodehalogenation under an atmosphere of 2. Iron-free metathesis/transmetallation with Alkyl-Grignard species: X equiv. R-MgX 1 TF, 0 C, t Scheme S8: Transmetallation. 2 Table S2: Iron-free transmetallation with commercial TF solutions of t-bumgcl and i-prmg. Entry X equiv. R-MgX t [h] 2 [%] equiv. t-bumgcl equiv. i-prmg

7 ydrodehalogenation with NaB 4 and LiAl 4 : 10 mol% Fe(acac) 3 5 equiv. M 1 M 2 4 TF, RT, 12 h M 1 = Li, M 2 = Al M 1 = Na, M 2 = B < 2% Scheme S9: Reductive dehalogenation with metal hydrides. Alternative pre-catalysts. 1 mol% [M], 1.5 equiv. t-bumgcl 1 TF, 0 C, 20 min 2 Scheme S10: Employment of different pre-catalysts. Table S3: Conversion and yield in hydrodehalogenations with various metal catalysts. Fe(acac) 3 FeCl 2 FeI 2 FeF 2 CoCl 2 Pd(acac) 2 Ni(acac) 2 CuCl 2 2 [%] [%] % Biphenyl Fe(acac)3 FeCl2 FeI2 FeF2 CoCl2 Pd(acac)2 Ni(acac)2 CuCl2 Figure S2: Yields of 2 after 20 min at 0 C (see Scheme S10).

8 Iron-catalyzed dehalogenation of alkyl halides. See standard conditions for reductive dehalogenation of aryl halides. R 1mol% Fe(acac) equiv. t-bumgcl TF, 0 C, 90 min Scheme S11: ydrodehalogenation of alkyl halides. R Dehalogenation of cinnamyl acetate. OAc 5 mol% Fe(acac) 3 5 Äquiv. t-bumgcl TF, 0 C, 90 min + 25 % 5 % Scheme S12: Attempted dehalogenation of cinnamyl acetate under standard conditions.

9 Phenyl pivalate: R f = 0.21 (SiO 2, cyclohexane : ethylacetate (99:1)); colorless oil. 1 NMR (300 Mz, CDCl 3 ) δ 1.39 (s, 9), 7.08 (d, J = 7.6 z, 2), 7.25 (quart, J = 5.2 z, 2), 7.40 (t, J = 8.1 z, 1); 13 C NMR (75 Mz, CDCl 3 ) δ 27.2, 29.7, 39.1, 121.5, 125.6, 129.3, GC-MS: R t = 5.27 min (GC-MS method M); m/z = 178, 135, 94, 85, 77, 65, 57, 51. O O O O

10 Methyl sulfanylbenzene: R f = 0.30 (SiO 2, cyclohexane : ethylacetate (99:1)); colorless oil. 1 NMR (300 Mz, CDCl 3 ) δ 7.31 (m, 5), 2.52 (s, 3); 13 C NMR (75 Mz, CDCl 3 ) δ 15.9, 125.0, 126.7, 128.8, GC- MS: R t = 4.33 min (GC-MS method M); m/z = 124, 109, 91, 78, 74, 65, S S

11 2-Methyl quinoline: R f = 0.62 (SiO 2, cyclohexane : ethylacetate (4:1)); colorless oil. 1 NMR (300 Mz, CDCl 3 ) δ 2.73 (s, 3), 7.24 (m, 1), 7.46 (m, 1), 7.66 (m, 1), 7.73 (m, 1), 8.01 (m, 2); 13 C NMR (75 Mz, CDCl 3 ) δ 25.4, 122.0, 125.6, 126.5, 127.5, 128.6, 129.4, 136.1, 147.9, GC-MS: R t = 6.01 min (GC-MS method M); m/z = 143, 128, 115, 101, 89, 75, 63. N N

12 Biphenyl: R f = 0.60 (SiO 2, cyclohexane : ethylacetate (9:1)); colorless crystals. 1 NMR (300 Mz, CDCl 3 ) δ 7.31 (t, J = 7.4 z, 2), 7.41 (t, J = 7.4 z, 4), 7.62 (d, J = 7.4 z, 4); 13 C NMR (75 Mz, CDCl 3 ) δ 127.4, 129.0, GC-MS: R t = 6.28 min (GC-MS method M); m/z = 154, 128, 115, 102, 76, 63.

13 2 NMR (77 Mz, TF-d 8 ): δ 7.24 (s). D

14 1 NMR (300 Mz, CDCl 3 ) δ 0.46 (s, 3), 1.01 (d, J = 4.8 z, 6), 1.13 (td, J = 4.7 z, 1), 1.38 (d, J = 10.6 z, 1), (m, 1 ), (m, 2), (m, 2), 5.88 (s, 1 ), 7.17 (t, J = 5.9 z, 1 ), 7.54 (d, J = 8.1 z, 1 ), 7.66 (t, J = 7.5 z, 1 ), 8.51 (d, J = 4.6 z, 1); 13 C NMR (75 Mz, CDCl 3 ) δ 17.2, 22.4, 24.5, 29.4, 32.6, 42.1, 46.1, 49.0, 51.9, 83.8, 121.5, 123.2, 135.1, O N O N

15 3,5-Dimethyl-2-phenylthiophene: 1 NMR (300 Mz, CDCl 3 ) δ (m, 5), 6.73 (s, 1), 2.58 (s, 3), 2.41 (s, 3). Ph S

16 Benzothiophene: R f = 0.47 (SiO 2, cyclohexane : ethylacetate (9:1)); yellow oil. 1 NMR (300 Mz, CDCl 3 ) δ 7.98 (m, 1), 7.92 (m, 1), 7.50 (m, 1), (m, 3); 13 C NMR (75 Mz, CDCl 3 ) δ 139.8, 139.7, 126.4, 124.3, 124.3, 123.9, 123.7, GC-MS: R t = 5.21 min (GC-MS method M); m/z = 134, 108, 89, 69, 63. S S

17 N ppm (f1) N ppm (f1)

18 O ppm (f1) O ppm (f1) 5.0

19 Biphenyl (M = g/mol). R t = 6.28 min (GC-MS method M) Methyl sulfanylbenzene (M = g/mol). R t = 4.33 min (GC-MS method M) S

20 Phenyl pivalate (M = g/mol). R t = 5.27 min (GC-MS method M) O O Quinaldine (M = 143 g/mol). R t = 6.01 min (GC-MS method M) N

21 Benzothiophene (M = g/mol). R t = 5.21 min (GC-MS method M) S 1-Chlorobutane (M = 92.0 g/mol). R t = 3.47 min (GC-MS method M) Cl