Practical Iron-Catalyzed Dehalogenation of Aryl Halides
Transcript of Practical Iron-Catalyzed Dehalogenation of Aryl Halides
Practical Iron-Catalyzed Dehalogenation of Aryl Halides
Waldemar Maximilian Czaplik, Sabine Gruppe, Matthias Mayer and Axel
Jacobi von Wangelin*
Department of Chemistry, University of Cologne
Greinstr. 4, 50939 Köln, Germany
Fax: (+) 49 (0)221 470 5057
E-mail: [email protected]
Homepage: www.jacobi.uni-koeln.de
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General. Analytical thin-layer chromatography. TLC was performed using aluminium plates with silica
gel and fluorescent indicator (Merck, 60F254). 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 (0.040-
0.063 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: HP-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. HP6890 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 Bruker DPX300
(300MHz).
IR spectroscopy. ATR technique (Thermo Nicolet 380 FT-IR). Intensity: s = strong, m =
medium und w = weak.
High resolution mass spectrometry (HRMS). Mass spectra were taken at Finnigan MAT 900s
(EI).
Trisacetylacetonato-iron(III) from Acros Organics (99+%, anhydrous, pure) was stored in a
Glovebox (MBraun 99.996% N2).
THF was dried over sodium with benzophenone as indicator (reflux, freshly destilled)
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Initial screening: Ethylmagnesium chloride.
Br
cat. Fe(acac)3Et-MgCl
THF, 0 °C, 1 h
1 2 3
+
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. 86 8
10 3 equiv. 83 8
10 1.2 equiv. 51 12
5 5 equiv. 87 6
5 3 equiv. 80 5
5 1.2 equiv. 62 10
1 1.2 equiv. 67 9
0.1 1.2 equiv. 38 14
0 1.2 equiv. 0 0
tert-Butylmagnesium chloride.
Br
1 mol% Fe(acac)3t-Bu-MgCl
THF, 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.
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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 THF (4 mL) was added, and the solution stirred at
0°C. tert-Butylmagnesium chloride (1.7 M in THF; 1.5 - 3 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 NH4Cl (2 mL), extracted with ethyl acetate (3 x 4 mL). The organic
phases were dried (Na2SO4) 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, H.-G. Schmalz, Synlett 2008, 1361.
For 4-deuterobiphenyl, see: Y. Miura, H. Oka, E. Yamano, M. Morita, J. Org. Chem. 1997,
62, 1188.
Hydrodehalogenation vs. Grignard formation. See Figure 1 in manuscript.
Hydrodehalogenation: 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). THF (12 mL) was added, and the reaction cooled
to 0°C. 4-Bromobiphenyl (3 mmol) was added dropwise with a syringe. Over a period of 2h,
samples (50 μL) were taken, filtered through SiO2 and analyzed by quantitative GC-FID
(internal reference n-pentadecane).
Deuteration experiments.
Br1 mol% Fe(acac)3
1.5 equiv. t-BuMgClTHF, 0 °C, 90 min
H
no D incorporation!
PhCHOrt, 0.5 h
rt, 0.5 h
D2O
HPh
OH
+
0% Scheme S3: Work-up with deuterium oxide (top) and benzaldehyde (bottom).
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Analysis of the crude reaction by 1H-, H,H-COSY, and 2H-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 THF-d8 as solvent and commercial t-ButylMgCl as a 1.7 M solution in
THF, the overall deuterium content of the solvent is 78%. With this solvent system, no
incorporation of deuterium into the reduction product was observed (1H-, H,H-COSY, and 2H-
NMR).
Br 1 mol% Fe(acac)3
1.5 equiv. t-BuMgCl
H
THF-d8, 0 °C, 90 minno D incorporation!
Scheme S4: Use of THF-d8 as solvent.
Preparation of C2D5MgBr:
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 THF (5 mL) and DiBAl-H (88 µL, 1 M in hexane, 0.088 mmol) were added via syringe,
and the reaction cooled to 0°C. After 5 min, bromoethane-d5 (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 (1H-, 2H-
NMR).
Two reaction runs with deuterated ethylmagnesium bromide (C2D5MgBr) afforded
exclusively 4-deuterobiphenyl (Scheme S5).
Br
DD
D
DD
MgBr
DD
D
DD
1.5 equiv. Mg1.2 equiv. LiCl
0.01 mol% DiBAlH
THF, 0°C, 2 h
Ph
Br
5 mol% Fe(acac)3
THF, 0 °C, 90 min Ph
D
100% Dincorporation!
0.5 equiv.
Scheme S5: Preparation of deuterated Ethyl-MgBr and deuterodehalogenation of 1.
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Alternative reductants. Grignard species without ß-hydrogen atoms:
1 mol% Fe(acac)31.5 equiv. MeMgCl
THF, 0 °C, 90 min
Br H
traces Scheme S6: Use of MeMgCl as reductant.
An identical result was obtained when employing 1.5 equiv. PhMgCl in THF as
stoichiometric reductant.
Pressurized H2:
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 THF (2 mL) and
TMEDA (80 mol%) were added, and the mixture cooled to 0°C. Then, ethylmagnesium
chloride (50 mol%, 1.5 M in THF) was added, the vial transferred to a 100mL Parr high-
pressure 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 NH4Cl (2 mL),
extracted with ethyl acetate (3 x 4 mL), and analyzed by quantitative GC-FID to document the
formation biphenyl with 18% yield.
Br
10 mol% Fe(acac)350 mol% EtMgCl80 mol% TMEDA
THF, rt, 50 bar H2 18% Scheme S7: Iron-catalyzed hydrodehalogenation under an atmosphere of H2.
Iron-free metathesis/transmetallation with Alkyl-Grignard species:
Br HX equiv. R-MgX
THF, 0 °C, t21
Scheme S8: Transmetallation.
Table S2: Iron-free transmetallation with commercial THF solutions of t-BuMgCl and i-PrMgBr.
Entry X equiv. R-MgX t [h] 2 [%] 1 2 0 2 4 0 3 18 0 4
1.5 equiv. t-BuMgCl
48 0 5 2 8 6 4 15 7
2.5 equiv. i-PrMgBr 24 17
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Hydrodehalogenation with NaBH4 and LiAlH4: 10 mol% Fe(acac)3
5 equiv. M1M2H4
THF, RT, 12 h
Br HM1 = Li, M2 = AlM1 = Na, M2 = B
< 2% Scheme S9: Reductive dehalogenation with metal hydrides.
Alternative pre-catalysts.
Br
1 mol% [M], 1.5 equiv. t-BuMgCl
2THF, 0 °C, 20 min
1 Scheme S10: Employment of different pre-catalysts.
Table S3: Conversion and yield in hydrodehalogenations with various metal catalysts.
0
10
20
30
40
50
60
70
80
Fe(aca
c)3FeC
l2FeI2
FeF2
CoCl2
Pd(aca
c)2
Ni(aca
c)2CuCl2
% Biphenyl
Figure S2: Yields of 2 after 20 min at 0°C (see Scheme S10).
Fe(acac)3 FeCl2 FeI2 FeF2 CoCl2 Pd(acac)2 Ni(acac)2 CuCl2 2 [%] 70 74 41 0 9 9 6 0 1 [%] 30 26 59 100 81 81 94 100
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Iron-catalyzed dehalogenation of alkyl halides. See standard conditions for reductive dehalogenation of aryl halides.
R Br
1 mol% Fe(acac)31.5 equiv. t-BuMgCl
THF, 0 °C, 90 minR H
Scheme S11: Hydrodehalogenation of alkyl halides.
Dehalogenation of cinnamyl acetate.
OAc5 mol% Fe(acac)35 Äquiv. t-BuMgCl
THF, 0 °C, 90 min+
25 % 5 % Scheme S12: Attempted dehalogenation of cinnamyl acetate under standard conditions.
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Phenyl pivalate: Rf = 0.21 (SiO2, cyclohexane : ethylacetate (99:1)); colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.39 (s, 9H), 7.08 (d, J = 7.6 Hz, 2H), 7.25 (quart, J = 5.2 Hz, 2H), 7.40 (t, J = 8.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 27.2, 29.7, 39.1, 121.5, 125.6, 129.3, 151.1. GC-MS: Rt = 5.27 min (GC-MS method 50-300M); m/z = 178, 135, 94, 85, 77, 65, 57, 51.
O
O
O
O
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Methyl sulfanylbenzene: Rf = 0.30 (SiO2, cyclohexane : ethylacetate (99:1)); colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.31 (m, 5H), 2.52 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 15.9, 125.0, 126.7, 128.8, 138.5. GC-MS: Rt = 4.33 min (GC-MS method 50-300M); m/z = 124, 109, 91, 78, 74, 65, 51.
2
.99
9
4.9
38
7.3
14
37
.30
50
7.2
80
7
2.5
15
5
S
S
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2-Methyl quinoline: Rf = 0.62 (SiO2, cyclohexane : ethylacetate (4:1)); colorless oil. 1H NMR (300 MHz, CDCl3) δ 2.73 (s, 3H), 7.24 (m, 1H), 7.46 (m, 1H), 7.66 (m, 1H), 7.73 (m, 1H), 8.01 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 25.4, 122.0, 125.6, 126.5, 127.5, 128.6, 129.4, 136.1, 147.9, 159.0. GC-MS: Rt = 6.01 min (GC-MS method 50-300M); m/z = 143, 128, 115, 101, 89, 75, 63.
N
N
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Biphenyl: Rf = 0.60 (SiO2, cyclohexane : ethylacetate (9:1)); colorless crystals. 1H NMR (300 MHz, CDCl3) δ 7.31 (t, J = 7.4 Hz, 2H), 7.41 (t, J = 7.4 Hz, 4H), 7.62 (d, J = 7.4 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ 127.4, 129.0, 141.5. GC-MS: Rt = 6.28 min (GC-MS method 50-300M); m/z = 154, 128, 115, 102, 76, 63.
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2H NMR (77 MHz, THF-d8): δ 7.24 (s).
D
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1H NMR (300 MHz, CDCl3) δ 0.46 (s, 3H), 1.01 (d, J = 4.8 Hz, 6H), 1.13 (td, J = 4.7 Hz, 1H), 1.38 (d, J = 10.6 Hz, 1H), 1.46-1.55 (m, 1 H), 1.81-1.93 (m, 2H), 2.25-2.42 (m, 2H), 5.88 (s, 1 H), 7.17 (t, J = 5.9 Hz, 1 H), 7.54 (d, J = 8.1 Hz, 1 H), 7.66 (t, J = 7.5 Hz, 1 H), 8.51 (d, J = 4.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) 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, 146.8.
NOH
NOH
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3,5-Dimethyl-2-phenylthiophene: 1H NMR (300 MHz, CDCl3) δ 7.60-7.40 (m, 5H), 6.73 (s, 1H), 2.58 (s, 3H), 2.41 (s, 3H).
SPh
H
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Benzothiophene: Rf = 0.47 (SiO2, cyclohexane : ethylacetate (9:1)); yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.98 (m, 1H), 7.92 (m, 1H), 7.50 (m, 1H), 7.47-7.41(m, 3H); 13C NMR (75 MHz, CDCl3) δ 139.8, 139.7, 126.4, 124.3, 124.3, 123.9, 123.7, 122.6. GC-MS: Rt = 5.21 min (GC-MS method 50-300M); m/z = 134, 108, 89, 69, 63.
S
S
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ppm (f1)050100150200
-5000
0
5000
10000
15000
20000
25000
30000146.
216
128.
850
117.
884
114.
656
NH H
ppm (f1)1.02.03.04.05.06.07.08.09.0
0
1000
2000
3000
4000
5000
7.41
57.
393
7.37
07.
008
6.98
56.
842
6.81
6
3.76
0
2.00
1.981.03
2.00
NH H
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OH
ppm (f1)050100150
0
5000
10000
155.
151
129.
684
120.
896
115.
323
ppm (f1)5.0
0
5000
7.33
07.
302
7.27
77.
030
7.00
56.
981
6.92
16.
895
5.66
7
2.00
1.012.00
1.04
OH
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Biphenyl (M = 154.1 g/mol). Rt = 6.28 min (GC-MS method 50-300M)
Methyl sulfanylbenzene (M = 124.0 g/mol). Rt = 4.33 min (GC-MS method 50-300M)
S
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Phenyl pivalate (M = 178.1 g/mol). Rt = 5.27 min (GC-MS method 50-300M)
Quinaldine (M = 143 g/mol). Rt = 6.01 min (GC-MS method 50-300M)
N
O
O
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Benzothiophene (M = 134.0 g/mol). Rt = 5.21 min (GC-MS method 50-300M)
1-Chlorobutane (M = 92.0 g/mol). Rt = 3.47 min (GC-MS method 50-300M)
Cl
S
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