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

Supplementary Material (ESI) for Chemical CommunicationsThis journal is (c) The Royal Society of Chemistry 2010

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)


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.


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).


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.


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


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


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.


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


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


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


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.


2H NMR (77 MHz, THF-d8): δ 7.24 (s).

D


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


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


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


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


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


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


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


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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Practical Iron-Catalyzed Dehalogenation of Aryl Halides

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