S1
Iron-catalyzed, Highly Regioselective, Synthesis of -Aryl Carboxylic Acids from Styrene Derivatives and CO2
Mark D. Greenhalgh, and Stephen P. Thomas*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, United Kingdom
Supporting Information
Table of Contents
General Experimental
S2
General Procedures
S3
Ligand Preparation: Analytical Data for 5, 6
S4
Synthesis of Styrene Derivatives: Analytical Data for 7e,f
S5
Table S1. Catalyst Identification
S7
Table S2. Reaction Scope and Limitations: Analytical Data for 2, 8a-l
S14
Mechanistic Investigations
S23
ICP Analysis, and Investigation of Potential Catalytic Role of Trace Metals
S30
NMR Traces: 5, 6, 7e-h, j, 2, 8a-o
S32
GC-MS Traces: 2, 8a-o
S59
References
S67
S2
General Experimental
All air and moisture sensitive manipulations were carried out using standard vacuum line and Schlenk
techniques, or in a drybox containing a purified argon atmosphere. Solvents for air and moisture
sensitive manipulations were obtained from an Anhydrous Engineering Solvent Purification System. All
glassware was cleaned using base (KOH, iPrOH) then acid (HClaq) baths.
Iron(II) chloride was purchased from Strem Chemicals Inc. (UK); anhydrous iron chloride, 98% (product
number 93-2631. Lot 19226800, 44.00000% Fe, expect 44.059%). Iron(II) chloride tetrahydrate was
purchased from Sigma Aldrich (UK); puriss. p.a., >99.0% (product number 44939. Lot BCBF5170V).
Iron(II) chloride 99.99% was purchased from Sigma Aldrich (UK); anhydrous beads, -10 mesh, 99.99%
(product number 450936). All styrene derivatives used were purchased from Sigma Aldrich, Alfa Aesar
and Tokyo Chemical Industries, UK, or synthesised within the laboratory. All Grignard reagents, d5-
Bromoethane, (1-bromoethyl)benzene and (2-bromoethyl)benzene were purchased from Sigma Aldrich
(UK). Carbon dioxide was purchased from BOC LTD (UK) (C40-VB – Carbon dioxide cylinder, vapour, B-
size 10).
1H, 13C and 19F NMR spectra were recorded on Varian VNMR 400 and 500MHz or Jeol Eclipse 300MHz
and 400MHz spectrometers. All spectra were obtained at ambient temperature. The chemical shifts (δ)
were recorded in parts per million (ppm) and the coupling constants (J) in Hertz (Hz). 1H and 13C NMR
multiplicity and coupling constants are reported where applicable. 1H and 13C spectra were referenced
to the residual deuterated solvent peak (CHCl3 7.27ppm, 77.00ppm).
Aqueous sulphate buffer was prepared by dissolving Na2SO4 (1.5 mol) H2SO4 (0.5 mol) and adding water
to give a total volume of 2000 cm3. Flash chromatography was performed on silica gel (Merck Kielselgel
60). Analytical thin layer chromatography was performed on aluminium backed silica plates (60 F254).
Gas chromatography was performed on an Agilent HP6890 gas chromatograph equipped with an Agilent
J&W DB-5ms capillary column (15 m × 0.25 mm × 0.25 µm). Several different methods were used:
[70-1]: Injector temp. 250 °C, 70 °C for 3 min, ramps 25 °C/min to 200 °C, ramps 45 °C/min to 250 °C,
holds for 3 min, ramps 45 °C/min to 300 °C, holds for 3 min.
[35-AJP]: Injector temp. 250 °C, 35 °C for 3 min, 45 °C/min to 250 °C, hold for 3 min, 45 °C/min to 300 °C,
hold for 3 min.
Infra-red spectra were recorded on a Perkin-Elmer Spectrum One FT-IR spectrometer. Melting points
were determined using a Stuart Scientific SMP10 and were uncorrected. High resolution mass spectra
were recorded on a VG autospec mass spectrometer.
S3
General Procedures
General procedure A: Synthesis of styrene derivatives
A benzaldehyde derivative (5 mmol) was added to potassium carbonate (1.1 g, 8 mmol) and
methyltriphenylphosphonium bromide (2.1 g, 6 mmol) in anhydrous 1,4-dioxane (5 mL), and heated at
reflux for 16 hours. The reaction mixture was cooled, filtered and concentrated in vacuo. The residue
was dissolved in hot n-pentane, cooled to 0 °C, filtered, and washed with cold n-pentane. The filtrate
was dried (MgSO4) and concentrated in vacuo to give the styrene derivative.
General procedure B: Catalyst optimisation
Styrene (80 µL, 0.7 mmol) was added to a solution of an iron salt and ligand in anhydrous
tetrahydrofuran (5 mL) at room temperature. The Grignard reagent (1.1 mmol) was added dropwise
over 10 minutes and the reaction stirred at room temperature under an atmosphere of nitrogen for 1
hour. Carbon dioxide was bubbled through the reaction via a needle for 30 minutes. Aqueous sulphate
buffer solution (10 mL) was added and the aqueous phase extracted with diethyl ether (3 x 20 mL). The
combined organic extracts were washed with H2O and brine, dried (MgSO4) and concentrated in vacuo
to give the crude reaction products. Dimethoxybenzene (19.3 mg, 0.14 mmol) was added as an internal
standard, and a yield for the reaction determined for 1H NMR.
All products were known, identified by 1H NMR, and characterised by comparison with authentic
samples of spectral data.
General procedure C: Hydrocarboxylation of styrene derivatives
A styrene derivative (0.7 mmol) was added to a solution of iron(II) chloride (0.9 mg, 0.007 mmol) and
2,6-bis-[1-(2,6-diisoprpylphenylimino)ethyl]pyridine 6 (3.4 mg, 0.007 mmol) in anhydrous
tetrahydrofuran (5 mL) at room temperature. Ethylmagnesium bromide (0.3 mL, 3M in Et2O, 0.9 mmol)
was added dropwise over 10 minutes and the reaction stirred at room temperature under an
atmosphere of nitrogen for 2 hours. Carbon dioxide was bubbled through the reaction via a needle for
30 minutes. Aqueous sulphate buffer solution (10 mL) was added and the aqueous phase extracted with
diethyl ether (3 x 20 mL). The combined organic extracts were washed with H2O and brine, dried
(MgSO4) and concentrated in vacuo to give the crude reaction products.
Known products were identified by 1H NMR, and characterised by comparison with authentic samples of
spectral data.
In order to determine isolated yields, sodium hydroxide (1M aqueous) was added to the crude reaction
products and extracted with diethyl ether (3 x 20 mL). The aqueous phase was acidified to pH 1 with
concentrated hydrochloric acid, and extracted with diethyl ether (3 x 20 mL). The combined organic
phases were washed with H2O and brine, dried (MgSO4) and concentrated in vacuo to give the purified
carboxylic acid product. If necessary, the product was further purified by flash silica chromatography.
S4
Ligand preparation
(±)-(N,N’-bis(pyridin-2-ylmethylene)cyclohexane-1,2-diamine1 5
2-Pyridinecarboxaldehyde (2.52 mL, 26.4 mmol) in anhydrous methanol (30 mL) was added to a solution
of (±)-trans-diaminocyclohexane (1.44 mL, 12 mmol) in anhydrous methanol (30 mL) and molecular
sieves (3 Å) at 0 °C under an atmosphere of nitrogen. The reaction mixture was shaken for 16 hours,
allowing the reaction to warm to room temperature over this time. The solution was filtered through
celite and the solvent removed in vacuo to give the crude product which was recrystallized from hot
ethanol to give (±)-(N,N’-bis(pyridin-2-ylmethylene)cyclohexane-1,2-diamine 5 (2.6 g, 74 %) as colourless
needles. m.p 139-141 °C (EtOH). δH (300 MHz, CDCl3) 8.56 (ddd, J= 4.8 Hz, 1.7 Hz, 1.0 Hz, 2H), 8.32 (s, 2H),
7.89 (dt, J= 7.9 Hz, 1.1 Hz, 2H), 7.65 (ddd, J= 7.7 Hz, 1.7 Hz, 0.6 Hz, 2H), 7.23 (ddd, J= 7.6 Hz, 4.8 Hz, 1.2
Hz, 2H), 3.60-3.49 (m, 2H), 1.95-1.78 (m, 6H), 1.58-1.46 (m, 2H). δC (100 MHz, CDCl3) 161.4, 154.6, 149.2,
136.4, 124.5, 121.3, 73.5, 32.7, 24.3. IR (neat) max cm-1 3053, 3007, 2936, 2851, 1644, 1586, 1567, 1467,
1436, 1370.
Data were in accordance with those previously reported in the literature.1
2,6-bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine2 6
2,6-Diisopropylaniline (10.9 mL, 58 mmol) was added to a stirred suspension of 2,6-diacetylpyridine (4.2
g, 26 mmol) and p-toluene sulfonic acid (0.3 g, 1.5 mmol) in anhydrous toluene (350 mL) and heated at
reflux under Dean-Stark conditions for 16 hours. The solvent was removed in vacuo and the yellow solid
recrystallized from dichloromethane by slow evaporation to give 2,6-bis-[1-(2,6-
diisopropylphenylimino)ethyl]pyridine 6 (9.1 g, 73%) as yellow needles. m.p 298-299 °C (CH2Cl2). δH (400
MHz, CDCl3) 8.50 (d, J= 7.8Hz, 2H), 7.95 (t, J= 7.8Hz, 1H), 7.21-7.17 (m, 4H), 7.15-7.09 (m, 2H), 2.79 (sept,
J= 6.9 Hz, 4H), 2.29 (s, 6H), 1.18 (d, J= 6.9 Hz, 24H). δC (125 MHz, CDCl3) 166.9, 155.1, 146.5, 136.8, 135.8,
123.6, 123.0, 122.2, 28.3, 23.2, 22.9, 17.1. IR (neat) max cm-1 3060, 2959, 2925, 2867, 1643, 1570, 1455,
1435, 1364.
Data were in accordance with those previously reported in the literature.2
S5
Synthesis of styrene derivatives
4-iso-Butylstyrene3 7e
According to general procedure A, 4-iso-butylbenzaldhyde (0.83 mL, 5 mmol), potassium carbonate (1.1
g, 8 mmol) and methyltriphenylphosphonium bromide (2.1 g, 6 mmol) in anhydrous 1,4-dioxane (5 mL)
were heated at reflux for 16 hours to give 4-iso-butylstyrene 7e as a colourless oil (666 mg, 84%). δH
(400 MHz, CDCl3) 7.37-7.32 (m, 2H), 7.15-7.10 (m, 2H), 6.72 (dd, J= 17.6 Hz, 10.9 Hz, 1H), 5.72 (dd, J=
17.6 Hz, 1.0 Hz, 1H), 5.21 (dd, J= 10.9 Hz, 1.0 Hz, 1H), 2.48 (d, J= 7.2 Hz, 2H), 1.88 (app. non, app J= 6.8
Hz, 1H), 0.92 (d, J= 6.6 Hz, 6H). δC (100 MHz, CDCl3) 141.5, 136.8, 135.1, 129.3, 125.9, 112.8, 45.2, 30.2,
22.3. IR (neat) max cm-1 3086, 3019, 2954, 2920, 2847, 1631, 1511, 1464, 1405, 1383, 1366.
Data were in accordance with those previously reported in the literature.3
3-(Benzyloxy)styrene4 7f
According to general procedure A, 3-benzyloxybenzaldhyde (1.06 g, 5 mmol), potassium carbonate (1.1
g, 8 mmol) and methyltriphenylphosphonium bromide (2.1 g, 6 mmol) in anhydrous 1,4-dioxane (5 mL)
were heated at reflux for 16 hours to give 3-benzyloxystyrene 7f as a colourless oil (934 mg, 89%). δH
(400 MHz, CDCl3) 7.49-7.45 (m, 2H), 7.44-7.39 (m, 2H), 7.38-7.32 (m, 2H), 7.30-7.24 (m, 1H), 7.09-7.03
(m, 2H), 6.93-6.89 (m, 1H), 6.71 (dd, J= 17.6 Hz, 10.9 Hz, 1H), 5.76 (dd, J= 17.6 Hz, 0.9 Hz, 1H), 5.27 (dd,
J= 10.9 Hz, 0.9 Hz, 1H), 5.10 (s, 2H) δC (100 MHz, CDCl3) 159.0, 139.1, 137.0, 136.7, 129.5, 128.6, 128.0,
127.5, 119.2, 114.21, 114.17, 112.6, 70.0. IR (neat) max cm-1 3032, 2867, 1597, 1575, 1487, 1441, 1258,
1241, 1155, 1025. HRMS (ESI+) calculated for C15H14ONa+ 233.0937. Found 233.0942.
Data were in accordance with those previously reported in the literature.4
2-Methoxystyrene5 7g
According to general procedure A, 2-methoxybenzaldhyde (670 mg, 5 mmol), potassium carbonate (1.1
g, 8 mmol) and methyltriphenylphosphonium bromide (2.1 g, 6 mmol) in anhydrous 1,4-dioxane (5 mL)
were heated at reflux for 16 hours to give 2-methoxystyrene 7g as a colourless oil (476 mg, 72%). δH
(400 MHz, CDCl3) 7.52-7.48 (m, 1H), 7.30-7.24 (m, 1H), 7.09 (dd, J= 17.7 Hz, 11.1 Hz, 1H), 6.99-6.94 (m,
S6
1H), 6.92-6.88 (m, 1H), 5.77 (dd, J= 17.7 Hz, 1.5 Hz, 1H), 5.30 (dd, J= 11.1 Hz, 1.5 Hz, 1H), 3.87 (s, 3H). δC
(100 MHz, CDCl3) 156.7, 131.8, 128.8, 126.7, 126.5, 120.6, 114.4, 110.8, 55.4.
Data were in accordance with those previously reported in the literature.5
3-Methoxystyrene5 7h
According to general procedure A, 3-methoxybenzaldhyde (670 mg, 5 mmol), potassium carbonate (1.1
g, 8 mmol) and methyltriphenylphosphonium bromide (2.1 g, 6 mmol) in anhydrous 1,4-dioxane (5 mL)
were heated at reflux for 16 hours to give 3-methoxystyrene 7h as a colourless oil (495 mg, 75%). δH
(400 MHz, CDCl3) 7.30-7.24 (m, 1H), 7.05-7.02 (m, 1H), 6.99-6.96 (m, 1H), 6.86-6.82 (m, 1H), 6.72 (dd, J=
17.5 Hz, 10.8 Hz, 1H), 5.77 (dd, J= 17.5 Hz, 1.0 Hz, 1H), 5.27 (dd, J= 10.8 Hz, 1.0 Hz, 1H), 3.84 (s, 3H). δC
(100 MHz, CDCl3) 159.8, 139.0, 136.8, 129.5, 118.9, 114.1, 113.4, 111.5, 55.2.
Data were in accordance with those previously reported in the literature.5
2,5-Dimethoxystyrene6 7j
According to general procedure A, 2,5-dimethoxybenzaldhyde (831 mg, 5 mmol), potassium carbonate
(1.1 g, 8 mmol) and methyltriphenylphosphonium bromide (2.1 g, 6 mmol) in anhydrous 1,4-dioxane (5
mL) were heated at reflux for 16 hours to give 2,5-dimethoxystyrene 7j as a colourless oil (623 mg, 76%).
δH (400 MHz, CDCl3) 7.07-7.05 (m, 1H), 7.05 (dd, J= 17.7 Hz, 11.1 Hz, 1H), 6.85-6.78 (m, 2H), 5.75 (dd, J=
17.7 Hz, 1.4 Hz, 1H), 5.29 (dd, J= 11.1 Hz, 1.4 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H). δC (100 MHz, CDCl3) 153.7,
151.2, 131.5, 127.6, 114.9, 113.8, 112.2, 111.8, 56.2, 55.7. IR (neat) max cm-1 3085, 2997,2941, 2906,
2833, 1625, 1580, 1492, 1463, 1426, 1418, 1282, 1217, 1179, 1161, 1119, 1058, 1038, 1024.
Data were in accordance with those previously reported in the literature.6
S7
Table S1. Catalyst identification for the hydrocarboxylation of styrenea
Yield (%)b
entry Iron salt Ligand RMgX 2 2
1 FeCl2 - EtMgClc <1 0
2 Fe(OTf)2 - EtMgClc 1 0
3 FeCl3 - EtMgClc 2 0
4 FeCl2d
- EtMgClc 2 <1
5 Fe(OTf)2d
- EtMgClc 59 2
6 FeCl2 NMP 3 EtMgClc 27 <1
7 FeCl2 TMEDA 4 EtMgClc 62 <1
8 FeCl2 PBu3 EtMgBrf 60 2
9 FeCl2 5 EtMgClc 66 0
10 FeCl2 6 EtMgClc 85 <1
11 FeCl2 6 i-PrMgCle
79 6 12 FeCl2 6 EtMgBr
f 98 (96)
g 1
13 FeCl2 6 Cyclopentyl-MgBrh
87 6 14
FeCl2 (1 mol%) 6 (1 mol%)
EtMgBr
f 97 <1
15i FeCl2 (0.1 mol%) 6 (0.1 mol%)
EtMgBr
f 97 1
16 FeCl2.4H2O (1 mol%) 6 (1 mol%)
EtMgBr
f 97 1
a Conditions: 0.7mmol 1, 5 mol% iron salt, 5 mol% ligand, THF (0.15M), rt, (i) 150 mol%
RMgX, 1h, (ii) CO2, 30 min. b Yield determined by
1H NMR using an internal standard.
c 2M
in THF. d Reaction heated at reflux.
e 1M in THF.
f 3M in Et2O.
g Isolated yield.
h 2M in Et2O.
i
3h reaction time.
According to general procedure B, styrene (80 µL, 0.7 mmol), an iron salt, ligand and Grignard reagent
were reacted in tetrahydrofuran for 1 hour, after which carbon dioxide was bubbled through the
reaction mixture. Dimethoxybenzene (19.3 mg, 0.14 mmol, 20 mol%) was added as an internal standard,
and a yield for the reaction determined for 1H NMR.
S8
Table S1, entry 1: FeCl2 (4.4 mg, 5 mol%), EtMgCl (2M in THF, 0.55 mL, 1.1 mmol)
Dimethoxybenzene (20 mol%): 6.85ppm (s, 4H); 2-Phenylpropionic acid: 1.53 (d, 3H); (0.01/3) × 20 = 0.07% Yield;
3-Phenylpropionic acid: 3.02-2.95 (m, 2H); 0% Yield
Table S1, entry 2: Fe(OTf)2 (12.4 mg, 5 mol%), EtMgCl (2M in THF, 0.55 mL, 1.1 mmol)
Dimethoxybenzene (20 mol%): 6.85ppm (s, 4H); 2-Phenylpropionic acid: 1.53 (d, 3H); (0.19/3) × 20 = 1.3% Yield;
3-Phenylpropionic acid: 3.02-2.95 (m, 2H); 0% Yield
Table S1, entry 3: FeCl3 (5.7 mg, 5 mol%), EtMgCl (2M in THF, 0.55 mL, 1.1 mmol)
Dimethoxybenzene (20 mol%): 6.85ppm (s, 4H); 2-Phenylpropionic acid: 1.53 (d, 3H); (0.33/3) × 20 = 2.2% Yield;
3-Phenylpropionic acid: 3.02-2.95 (m, 2H); 0% Yield
S9
Table S1, entry 4: FeCl2 (4.4 mg, 5 mol%), EtMgCl (2M in THF, 0.55 mL, 1.1 mmol), heated at reflux
Dimethoxybenzene (20 mol%): 6.85ppm (s, 4H); 2-Phenylpropionic acid: 1.53 (d, 3H); (0.36/3) × 20 = 2.4% Yield;
3-Phenylpropionic acid: 3.02-2.95 (m, 2H); (0.03/2) × 20 = 0.3% Yield
Table S1, entry 5: Fe(OTf)2 (12.4 mg, 5 mol%), EtMgCl (2M in THF, 0.55 mL, 1.1 mmol), heated at reflux
Dimethoxybenzene (20 mol%): 6.85ppm (s, 4H); 2-Phenylpropionic acid: 1.53 (d, 3H); (8.79/3) × 20 = 58.6% Yield;
3-Phenylpropionic acid: 3.02-2.95 (m, 2H); (0.24/2) × 20 = 2.4% Yield
Table S1, entry 6: FeCl2 (4.4 mg, 5 mol%), N-methylpyrrolidone (20 µL, 30mol%), EtMgCl (2M in THF,
0.55 mL, 1.1 mmol)
Dimethoxybenzene (20 mol%): 6.85ppm (s, 4H); 2-Phenylpropionic acid: 1.53 (d, 3H); (4.11/3) × 20 = 27.4% Yield;
3-Phenylpropionic acid: 3.02-2.95 (m, 2H); (0.05/2) × 20 = 0.5% Yield
S10
Table S1, entry 7: FeCl2 (4.4 mg, 5 mol%), tetramethylethylenediamine (25 µL, 25mol%), EtMgCl (2M in
THF, 0.55 mL, 1.1 mmol)
Dimethoxybenzene (20 mol%): 6.85ppm (s, 4H); 2-Phenylpropionic acid: 1.53 (d, 3H); (9.34/3) × 20 = 62.3% Yield;
3-Phenylpropionic acid: 3.02-2.95 (m, 2H); (0.05/2) × 20 = 0.5% Yield
Table S1, entry 8: FeCl2 (4.4 mg, 5 mol%), tributylphosphine (35 µL, 20 mol%), EtMgBr (3M in Et2O,
0.35 mL, 1.1 mmol)
Trimethoxybenzene (20 mol%): 6.11ppm (s, 3H); 2-Phenylpropionic acid: 1.53 (d, 3H); (8.96/3) × 20 = 59.7% Yield;
3-Phenylpropionic acid: 3.02-2.95 (m, 2H); (0.19/2) × 20 = 1.9% Yield
Table S1, entry 9: FeCl2 (4.4 mg, 5 mol%), (±)-(N,N’-bis(pyridin-2-ylmethylene)cyclohexane-1,2-diamine
5 (10.2 mg, 5 mol%), EtMgCl (2M in THF, 0.55 mL, 1.1 mmol)
Dimethoxybenzene (20 mol%): 6.85ppm (s, 4H); 2-Phenylpropionic acid: 1.53 (d, 3H); (9.83/3) × 20 = 65.5% Yield;
3-Phenylpropionic acid: 3.02-2.95 (m, 2H); 0% Yield
S11
Table S1, entry 10: FeCl2 (4.4 mg, 5 mol%), 2,6-bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine 6
(16.9 mg, 5 mol%), EtMgCl (2M in THF, 0.55 mL, 1.1 mmol)
Dimethoxybenzene (20 mol%): 6.85ppm (s, 4H); 2-Phenylpropionic acid: 1.53 (d, 3H); (12.79/3) × 20 = 85.3% Yield;
3-Phenylpropionic acid: 3.02-2.95 (m, 2H); (0.01/2) × 20 = 0.1% Yield
Table S1, entry 11: FeCl2 (4.4 mg, 5 mol%), 2,6-bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine 6
(16.9 mg, 5 mol%), iPrMgCl (1M in THF, 1.1 mL, 1.1 mmol)
Dimethoxybenzene (20 mol%): 6.85ppm (s, 4H); 2-Phenylpropionic acid: 1.53 (d, 3H); (11.91/3) × 20 = 79.4% Yield;
3-Phenylpropionic acid: 3.02-2.95 (m, 2H); (0.55/2) × 20 = 5.5% Yield
Table S1, entry 12: FeCl2 (4.4 mg, 5 mol%), 2,6-bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine 6
(16.9 mg, 5 mol%), EtMgBr (3M in Et2O, 0.35 mL, 1.1 mmol)
Dimethoxybenzene (20 mol%): 6.85ppm (s, 4H); 2-Phenylpropionic acid: 1.53 (d, 3H); (14.64/3) × 20 = 97.6% Yield;
3-Phenylpropionic acid: 3.02-2.95 (m, 2H); (0.13/2) × 20 = 1.3% Yield
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Table S1, entry 13: FeCl2 (4.4 mg, 5 mol%), 2,6-bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine 6
(16.9 mg, 5 mol%), cyclopentylMgBr (2M in Et2O, 0.55 mL, 1.1 mmol)
Dimethoxybenzene (20 mol%): 6.85ppm (s, 4H); 2-Phenylpropionic acid: 1.53 (d, 3H); (13.04/3) × 20 = 86.9% Yield;
3-Phenylpropionic acid: 3.02-2.95 (m, 2H); (0.61/2) × 20 = 6.1% Yield
Table S1, entry 14: FeCl2 (0.9 mg, 1 mol%), 2,6-bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine 6 (3.4
mg, 1 mol%), EtMgBr (3M in Et2O, 0.35 mL, 1.1 mmol)
Dimethoxybenzene (20 mol%): 6.85ppm (s, 4H); 2-Phenylpropionic acid: 1.53 (d, 3H); (14.61/3) × 20 = 97.4% Yield;
3-Phenylpropionic acid: 3.02-2.95 (m, 2H); (0.13/2) × 20 = 1.3% Yield
Table S1, entry 15: FeCl2 (0.9 mg, 1 mol%), 2,6-bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine 6 (3.4
mg, 1 mol%) in THF (10 mL). 1 mL (0.1 mol% catalyst) sample taken for use in reaction. EtMgBr (3M in
Et2O, 0.35 mL, 1.1 mmol). Reaction left for 3 hours before CO2.
Dimethoxybenzene (20 mol%): 6.85ppm (s, 4H); 2-Phenylpropionic acid: 1.53 (d, 3H); (14.52/3) × 20 = 96.8% Yield;
3-Phenylpropionic acid: 3.02-2.95 (m, 2H); (0.10/2) × 20 = 1.0% Yield
S13
Table S1, entry 16: FeCl2.4H2O (1.4 mg, 1 mol%), 2,6-bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine
6 (3.4 mg, 1 mol%), EtMgBr (3M in Et2O, 0.35 mL, 1.1 mmol)
Dimethoxybenzene (20 mol%): 6.85ppm (s, 4H); 2-Phenylpropionic acid: 1.53 (d, 3H); (14.58/3) × 20 = 97.2% Yield;
3-Phenylpropionic acid: 3.02-2.95 (m, 2H); (0.07/2) × 20 = 0.7% Yield
Variation in solvent and temperature
The reaction was attempted in diethyl ether, acetonitrile and toluene at room temperature under
otherwise optimised conditions, however in each case no conversion of styrene to 2-phenylpropanoic
acid was observed. The reaction at 0 °C in tetrahydrofuran resulted in <10% 2-phenylpropanoic acid. At -
20 °C and -40 °C no reaction was observed. Raising the temperature to 45 °C in tetrahydrofuran resulted
in slightly lower yields than that observed at room temperature.
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Table S2. Iron-catalyzed hydrocarboxylation of styrene derivatives: scope and limitationsa
a
Conditions: 0.7mmol 1, 7a-l, 1 mol% FeCl2, 1 mol% 6, THF (0.15M), rt, (i) 120 mol% EtMgBr (3M in Et2O), 2h (ii) CO2, 30 min.
b 120 mol% Cyclopentylmagnesium bromide used (2M in Et2O).
2-Phenylpropanoic acid7 2
According to general procedure C, styrene (80 µL, 0.7 mmol), iron(II) chloride (0.9 mg, 0.007 mmol), 2,6-
bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine 6 (3.4 mg, 0.007 mmol), ethylmagnesium bromide (3M
in Et2O, 0.3 mL, 0.9 mmol) and carbon dioxide were reacted in anhydrous tetrahydrofuran to give the
crude reaction product, which was purified by acid-base work-up to give 2-phenylpropanoic acid 2 as a
colourless oil (101 mg, 0.67 mmol, 96%). δH (400 MHz, CDCl3) 11.38 (s, br, 1H), 7.40-7.26 (m, 5H), 3.75 (q,
J= 7.2Hz, 1H), 1.53 (d, J= 7.2Hz, 3H). δC (100 MHz, CDCl3) 180.9, 139.7, 128.7, 127.6, 127.4, 45.3, 18.1. IR
(neat) max cm-1 3030, 2980, 2937, 1702, 1496, 1453, 1413, 1230. GC-MS [70-1] (M+, relative abundance):
5.75 min (150, 99%).
Data were in accordance with those previously reported in the literature.7
S15
2-(4-Methylphenyl)propanoic acid7 8a
According to general procedure C, 4-methylstyrene (93 µL, 0.7 mmol), iron(II) chloride (0.9 mg, 0.007
mmol), 2,6-bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine 6 (3.4 mg, 0.007 mmol), ethylmagnesium
bromide (3M in Et2O, 0.3 mL, 0.9 mmol) and carbon dioxide were reacted in anhydrous tetrahydrofuran
to give the crude reaction product, which was purified by acid-base work-up to give 2-(4-
methylphenyl)propanoic acid 8a as a colourless amorphous solid (107 mg, 0.63 mmol, 90%). m.p. 34-
35 °C (CH2Cl2). δH (300 MHz, CDCl3) 11.27 (s, br, 1H), 7.27-7.20 (m, 2H), 7.20-7.13 (m, 2H), 3.72 (q, J=
7.2Hz, 1H), 2.34 (s, 3H), 1.51 (d, J= 7.2Hz, 3H). δC (75 MHz, CDCl3) 181.0, 137.1, 136.8, 129.4, 127.4, 44.9,
21.0, 18.1. IR (neat) max/cm-1 2983, 2940, 2920, 2735, 2631, 2546, 1695, 1513, 1418, 1231. GC-MS [70-
1] (M+, relative abundance): 6.35 min (164, 96%).
Data were in accordance with those previously reported in the literature.7
2-(3-Methylphenyl)propanoic acid 8b
According to general procedure C, 3-methylstyrene (93 µL, 0.7 mmol), iron(II) chloride (0.9 mg, 0.007
mmol), 2,6-bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine 6 (3.4 mg, 0.007 mmol), ethylmagnesium
bromide (3M in Et2O, 0.3 mL, 0.9 mmol) and carbon dioxide were reacted in anhydrous tetrahydrofuran
to give the crude reaction product, which was purified by acid-base work-up to give 2-(3-
methylphenyl)propanoic acid 8b as colourless needles (107 mg, 0.65 mmol, 93%). m.p. 62-63 °C (CH2Cl2).
δH (400 MHz, CDCl3) 11.03 (s, br, 1H), 7.26-7.21 (m, 1H), 7.16-7.08 (m, 3H), 3.72 (q, J= 7.2Hz, 1H), 2.36 (s,
3H), 1.52 (d, J= 7.2Hz, 3H). δC (100 MHz, CDCl3) 180.5, 139.7, 138.4, 128.6, 128.3, 128.2, 124.6, 45.2,
21.4, 18.1. IR (neat) max/cm-1 3023, 2980, 2935, 2722, 2619, 1695, 1454, 1321, 1244, 1221. GC-MS [70-
1] (M+, relative abundance): 6.28 min (164, 99%). HRMS (ESI-) calculated for C10H11O2- 163.0765. Found
163.0766.
S16
2-(2-Methylphenyl)propanoic acid7 8c
According to general procedure C, 2-methylstyrene (90 µL, 0.7 mmol), iron(II) chloride (0.9 mg, 0.007
mmol), 2,6-bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine 6 (3.4 mg, 0.007 mmol), ethylmagnesium
bromide (3M in Et2O, 0.3 mL, 0.9 mmol) and carbon dioxide were reacted in anhydrous tetrahydrofuran
to give the crude reaction product, which was purified by flash silica chromatography (8:1 hexanes:ethyl
acetate) to give 2-(2-methylphenyl)propanoic acid 8c as a colourless amorphous solid (78 mg, 0.48 mmol,
68%). Rf = 0.22 (4:1 hexanes:ethyl acetate). δH (500 MHz, CDCl3) 7.32-7.29 (m, 1H), 7.23-7.16 (m, 3H),
4.00 (q, J= 7.2Hz, 1H), 2.39 (s, 3H), 1.50 (d, J= 7.2Hz, 3H). δC (125 MHz, CDCl3) 180.1, 138.3, 135.9, 130.5,
127.2, 126.6, 126.5, 41.0, 19.6, 17.5. GC-MS [70-1] (M+, relative abundance): 6.33 min (164, 93%).
Data were in accordance with those previously reported in the literature.7
2-(4-tert-Butylphenyl)propanoic acid 8d
According to general procedure C, 4-tert-butylstyrene (128 µL, 0.7 mmol), iron(II) chloride (0.9 mg, 0.007
mmol), 2,6-bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine 6 (3.4 mg, 0.007 mmol), ethylmagnesium
bromide (3M in Et2O, 0.3 mL, 0.9 mmol) and carbon dioxide were reacted in anhydrous tetrahydrofuran
to give the crude reaction product, which was purified by acid-base work-up to give 2-(4-tert-
butylphenyl)propanoic acid 8d as colourless needles (112 mg, 0.54 mmol, 78%). m.p. 100-102 °C (CH2Cl2).
δH (400 MHz, CDCl3) 7.38-7.34 (m, 2H), 7.29-7.24 (m, 2H), 3.73 (q, J= 7.2Hz, 1H), 1.52 (d, J= 7.2Hz, 3H),
1.32 (s, 9H). δC (100 MHz, CDCl3) 181.0, 137.1, 136.8, 129.4, 127.4, 44.9, 21.0, 18.1. IR (neat) max/cm-1
2965, 2905, 2870, 1693, 1509, 1458, 1413, 1285, 1262, 1229. GC-MS [70-1] (M+, relative abundance):
7.33 min (206, 99%).
Data were in accordance with those previously reported in the literature.8
2-(4-iso-Butylphenyl)propanoic acid 8e
According to general procedure C, 4-iso-butylstyrene (112 mg, 0.7 mmol), iron(II) chloride (0.9 mg, 0.007
mmol), 2,6-bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine 6 (3.4 mg, 0.007 mmol), ethylmagnesium
S17
bromide (3M in Et2O, 0.3 mL, 0.9 mmol) and carbon dioxide were reacted in anhydrous tetrahydrofuran
to give the crude reaction product, which was purified by acid-base work-up to give 2-(4-iso-
butylphenyl)propanoic acid 8e as colourless needles (120 mg, 0.58 mmol, 83%). m.p. 76-77 °C (CH2Cl2).
δH (500 MHz, CDCl3) 11.74 (s, br, 1H), 7.26-7.22 (m, 2H), 7.14-7.10 (m, 2H), 3.73 (q, J= 7.2Hz, 1H), 2.47 (d,
J= 7.2Hz, 2H), 1.87 (m, 1H), 1.52 (d, J= 7.2Hz, 3H), 0.92 (d, J= 6.6Hz, 6H). δC (125 MHz, CDCl3) 181.0, 137.1,
136.8, 129.4, 127.4, 44.9, 21.0, 18.1. IR (neat) max/cm-1 3047, 2955, 2924, 2869, 2727, 1708, 1507, 1462,
1418, 1379, 1321, 1230. GC-MS [70-1] (M+, relative abundance): 7.38 min (206, 97%).
Data were in accordance with those previously reported in the literature.9
2-(3-(Benzyloxy)phenyl)propanoic acid 8f
According to general procedure C, 3-(benzyloxy)styrene (147 mg, 0.7 mmol), iron(II) chloride (0.9 mg,
0.007 mmol), 2,6-bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine 6 (3.4 mg, 0.007 mmol),
ethylmagnesium bromide (3M in Et2O, 0.3 mL, 0.9 mmol) and carbon dioxide were reacted in anhydrous
tetrahydrofuran to give the crude reaction product, which was purified by acid-base work-up to give 2-
(3-(benzyloxy)phenyl)propanoic acid 8f a colourless amorphous solid (129 mg, 0.50 mmol, 72%). m.p.
121-123 °C (CH2Cl2). δH (400 MHz, CDCl3) 10.29 (s, br, 1H), 7.46-7.42 (m, 2H), 7.41-7.37 (m, 2H), 7.35-7.31
(m, 1H), 7.28-7.24 (m, 1H), 6.99-6.97 (m, 1H), 6.95-6.92 (m, 1H), 6.91-6.88 (m, 1H), 5.06 (s, 2H), 3.73 (q,
J= 7.2Hz, 1H), 1.52 (d, J= 7.2Hz, 3H). δC (125 MHz, CDCl3) 178.8, 159.0, 141.3, 136.9, 129.7, 128.6, 128.0,
127.6, 120.2, 114.4, 133.5, 70.0, 45.1, 18.1. IR(neat) max/cm-1 3032, 2972, 2915, 2725, 2621, 2541, 1704,
1595, 1495, 1447, 1385, 1268, 1250, 1225, 1164, 1021. HRMS (ESI-) calculated for C16H15O3- 255.1027.
Found 255.1031.
2-(2-Methoxyphenyl)propanoic acid 8g
According to general procedure C, 2-vinylanisole (94 mg, 0.7 mmol), iron(II) chloride (0.9 mg, 0.007
mmol), 2,6-bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine 6 (3.4 mg, 0.007 mmol), ethylmagnesium
bromide (3M in Et2O, 0.3 mL, 0.9 mmol) and carbon dioxide were reacted in anhydrous tetrahydrofuran
to give the crude reaction product, which was purified by acid-base work-up to give 2-(2-
methoxyphenyl)propanoic acid 8g as a colourless amorphous solid (117 mg, 0.65 mmol, 93%). m.p. 101-
102 °C (CH2Cl2). δH (400 MHz, CDCl3) 11.45 (s, br, 1H), 7.33-7.22 (m, 2H), 7.01-6.93 (m, 1H), 6.92-6.87 (m,
S18
1H), 4.10 (q, J= 7.2Hz, 1H), 3.84 (s, 3H), 1.50 (d, J= 7.2Hz, 3H). δC (100 MHz, CDCl3) 180.7, 156.7, 128.7,
128.3, 128.0, 120.8, 110.7, 55.5. 39.1, 16.8. GC-MS [70-1] (M+, relative abundance): 6.75 min (180, 99%).
Data were in accordance with those previously reported in the literature.7
2-(3-Methoxyphenyl)propanoic acid 8h
According to general procedure C, 3-vinylanisole (94 mg, 0.7 mmol), iron(II) chloride (0.9 mg, 0.007
mmol), 2,6-bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine 6 (3.4 mg, 0.007 mmol), ethylmagnesium
bromide (3M in Et2O, 0.3 mL, 0.9 mmol) and carbon dioxide were reacted in anhydrous tetrahydrofuran
to give the crude reaction product, which was purified by acid-base work-up to give 2-(3-
methoxyphenyl)propanoic acid 8h as a yellow oil (115 mg, 0.64 mmol, 91%). m.p. 53-54 °C (CH2Cl2). δH
(400 MHz, CDCl3) 11.34 (s, br, 1H), 7.32-7.28 (m, 1H), 6.97-6.93 (m, 1H), 6.92-6.90 (m, 1H), 6.88-6.84 (m,
1H), 3.84 (s, 3H), 3.76 (q, J= 7.2Hz, 1H), 1.55 (d, J= 7.2Hz, 3H). δC (100 MHz, CDCl3) 180.1, 159.8, 141.2,
129.6, 119.9, 113.4, 112.7, 55.2, 45.3, 18.1. GC-MS [70-1] (M+, relative abundance): 6.97 min (180, 98%).
Data were in accordance with those previously reported in the literature.10
2-(4-Methoxyphenyl)propanoic acid 8i
According to general procedure C, 4-vinylanisole (93 µL, 0.7 mmol), iron(II) chloride (0.9 mg, 0.007
mmol), 2,6-bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine 6 (3.4 mg, 0.007 mmol), ethylmagnesium
bromide (3M in Et2O, 0.3 mL, 0.9 mmol) and carbon dioxide were reacted in anhydrous tetrahydrofuran
to give the crude reaction product, which was purified by acid-base work-up to give 2-(4-
methoxyphenyl)propanoic acid 8i as a yellow amorphous solid (69 mg, 0.39 mmol, 55%). m.p. 53-54 °C
(CH2Cl2). δH (300 MHz, CDCl3) 10.17 (s, br, 1H), 7.29-7.22 (m, 2H), 6.91-6.83 (m, 2H), 3.80 (s, 3H), 3.70 (q,
J= 7.2Hz, 1H), 1.50 (d, J= 7.2Hz, 3H). δC (75 MHz, CDCl3) 180.7, 158.9, 131.8, 128.6, 114.1, 55.3, 44.4, 18.1.
IR(neat) max/cm-1 3035, 2836, 1704, 1512, 1302, 1248, 1180. GC-MS [70-1] (M+, relative abundance):
7.03 min (180, 92%).
Data were in accordance with those previously reported in the literature.7
S19
2-(2,5-Dimethoxyphenyl)propanoic acid 8j
According to general procedure C, 2,5-dimethoxystyrene (115 mg, 0.7 mmol), iron(II) chloride (0.9 mg,
0.007 mmol), 2,6-bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine 6 (3.4 mg, 0.007 mmol),
ethylmagnesium bromide (3M in Et2O, 0.3 mL, 0.9 mmol) and carbon dioxide were reacted in anhydrous
tetrahydrofuran to give the crude reaction product, which was purified by acid-base work-up to give 2-
(2,5-dimethoxyphenyl)propanoic acid 8j as a colourless amorphous solid (137 mg, 0.65 mmol, 93%). m.p.
102-104 °C (Ethyl acetate/hexane). δH (400 MHz, CDCl3) 11.46 (br, 1H), 6.86-6.81 (m, 2H), 6.80-6.76 (m,
1H), 4.07 (q, J= 7.2Hz, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 1.48 (d, J= 7.2Hz, 3H). δC (125 MHz, CDCl3) 180.3,
153.7, 150.9, 129.8, 114.6, 112.3, 111.9, 56.2, 55.7, 39.1, 16.8. IR(neat) max/cm-1 2984, 2938, 2837, 2719,
2623, 1703, 1611, 1589, 1497, 1455, 1406, 1239, 1219, 1180, 1159, 1044, 1023. GC-MS [70-1] (M+,
relative abundance): 7.77 min (210, 99%).
Data were in accordance with those previously reported in the literature.7
2-(3,4-Dimethoxyphenyl)propanoic acid 8k
According to general procedure C, 3,4-dimethoxystyrene (104 µL, 0.7 mmol), iron(II) chloride (0.9 mg,
0.007 mmol), 2,6-bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine 6 (3.4 mg, 0.007 mmol),
ethylmagnesium bromide (3M in Et2O, 0.3 mL, 0.9 mmol) and carbon dioxide were reacted in anhydrous
tetrahydrofuran to give the crude reaction product, which was purified by flash silica chromatography
(7:1 hexanes:ethyl acetate) to give 2-(3,4-dimethoxyphenyl)propanoic acid 8k as a yellow amorphous
solid (38 mg, 0.18 mmol, 26%). δH (500 MHz, CDCl3) 6.90-6.80 (m, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 3.70 (q,
J= 7.2Hz, 1H), 1.52 (d, J= 7.2Hz, 3H). δC (125 MHz, CDCl3) 179.8, 149.0, 148.4, 132.3, 119.7, 111.2, 110.8,
55.9, 55.9, 44.8, 18.2. GC-MS [70-1] (M+, relative abundance): 7.85 min (210, 92%). HRMS (ESI-)
calculated for C11H13O4- 209.0819. Found 209.0826.
S20
2-(2-Biphenyl)propanoic acid 8l
According to general procedure C, 4-vinylbiphenyl (126 mg, 0.7 mmol, added as a tetrahydrofuran
solution (1mL)), iron(II) chloride (0.9 mg, 0.007 mmol), 2,6-bis-[1-(2,6-diisopropylphenylimino)
ethyl]pyridine 6 (3.4 mg, 0.007 mmol), ethylmagnesium bromide (3M in Et2O, 0.3 mL, 0.9 mmol) and
carbon dioxide were reacted in anhydrous tetrahydrofuran to give the crude reaction product, which
was purified by acid-base work-up to give 2-(2-biphenyl)propanoic acid 8l as a yellow amorphous solid
(63 mg, 0.28 mmol, 40%). m.p. 142-144 °C (CH2Cl2). δH (400 MHz, CDCl3) 10.17 (s, br, 1H), 7.60-7.55 (m,
4H), 7.47-7.39 (m, 4H), 7.38-7.33 (m, 1H), 3.81 (q, J= 7.2Hz, 1H), 1.57 (d, J= 7.2Hz, 3H). δC (100 MHz,
CDCl3) 180.2, 140.7, 140.4, 138.8, 128.7, 128.0, 127.4, 127.3, 127.1, 45.0, 18.1. IR(neat) max/cm-1 3032,
2982, 2919, 2849, 2622, 1693, 1486, 1409. GC-MS [70-1] (M+, relative abundance): 9.04 min (226,
99%).HRMS (ESI-) calculated for C15H13O2- 225.0921. Found 225.0920.
Data were in accordance with those previously reported in the literature.11
2-(4-Fluorophenyl)propanoic acid 8m
According to general procedure C, 4-fluorostyrene (83 µL, 0.7 mmol), iron(II) chloride (0.9 mg, 0.007
mmol), 2,6-bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine 6 (3.4 mg, 0.007 mmol), ethylmagnesium
bromide (3M in Et2O, 0.3 mL, 0.9 mmol) and carbon dioxide were reacted in anhydrous tetrahydrofuran
to give the crude reaction product, which was purified by flash silica chromatography (8:1 hexanes:ethyl
acetate) to give 2-(4-fluorophenyl)propanoic acid 8m as a colourless oil (44 mg, 0.26 mmol, 37%). δH
(500 MHz, CDCl3) 7.32-7.27 (m, 2H), 7.05-6.99 (m, 2H), 3.74 (q, J= 7.2Hz, 1H), 1.51 (d, J= 7.2Hz, 3H). δC
(125 MHz, CDCl3) 180.1, 162.1 (d, J= 246Hz), 135.4 (d, J= 3Hz), 129.2 (d, J= 8Hz), 115.5 (d, J= 21Hz),
44.5, 18.2. δF (470 MHz, CDCl3) -115.3. GC-MS [70-1] (M+, relative abundance): 5.78 min (168, 97%).
HRMS (ESI-) calculated for C9H8FO2- 167.0514. Found 167.0520.
S21
2-(2,4-Dimethylphenyl)propanoic acid and 3-(2,4-dimethylphenyl)propanoic acid 8n
According to general procedure C, 2,4-dimethylstyrene (102 µL, 0.7 mmol), iron(II) chloride (0.9 mg,
0.007 mmol), 2,6-bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine 6 (3.4 mg, 0.007 mmol),
ethylmagnesium bromide (3M in Et2O, 0.3 mL, 0.9 mmol) and carbon dioxide were reacted in anhydrous
tetrahydrofuran to give the crude reaction product, which was purified by acid-base work-up to give 2-
(2,4-dimethylphenyl)propanoic acid and 3-(2,4-dimethylphenyl)propanoic acid as a colourless
amorphous solid (56 mg, 0.32 mmol, 45%, : 20:25). The isomers were separated by flash silica
chromatography (0.01:8:1 acetic acid:hexanes:ethyl acetate).
When ethylmagnesium bromide was replaced with cyclopentylmagnesium bromide (2M in Et2O, 0.45 mL,
0.9 mmol), 2-(2,4-dimethylphenyl)propanoic acid and 3-(2,4-dimethylphenyl)propanoic acid were
produced as a colourless amorphous solid (92 mg, 0.52 mmol, 74%, : 13:61).
2-(2,4-Dimethylphenyl)propanoic acid: m.p. 106-108 °C (CH2Cl2). δH (400 MHz, CDCl3) 7.21-7.17 (m, 1H),
7.05-6.99 (m, 2H), 3.96 (q, J= 7.2Hz, 1H), 3.35 (s, 3H), 3.30 (s, 3H), 1.49 (d, J= 7.2Hz, 3H). δC (100 MHz,
CDCl3) 180.5, 136.8, 135.7, 135.4, 131.3, 127.1, 126.5, 40.7, 20.9, 19.5, 17.6. GC-MS [70-1] (M+, relative
abundance): 6.75 min (178, 96%). HRMS (ESI-) calculated for C11H13O2- 177.0921. Found 177.0927.
3-(2,4-Dimethylphenyl)propanoic acid: δH (400 MHz, CDCl3) 10.97 (s, br, 1H), 7.08-7.03 (m, 2H), 7.01-
6.94 (m, 2H), 2.97-2.90 (m, 2H), 2.67-2.60 (m, 2H), 2.30 (s, 6H). δC (125 MHz, CDCl3) 178.4, 136.0, 135.8,
135.2, 131.2, 128.4, 126.8, 34.4, 27.6, 20.9, 19.1. IR(neat) max/cm-1 2977, 2917, 2714, 2622, 1699, 1431,
1406, 1313, 1279, 1216. GC-MS [70-1] (M+, relative abundance): 7.02 min (178, 96%). HRMS (ESI-)
calculated for C11H13O2- 177.0921. Found 177.0926.
2-(2,5-Dimethylphenyl)propanoic acid and 3-(2,5-dimethylphenyl)propanoic acid 8o
According to general procedure C, 2,5-dimethylstyrene (102 µL, 0.7 mmol), iron(II) chloride (0.9 mg,
0.007 mmol), 2,6-bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine 6 (3.4 mg, 0.007 mmol),
ethylmagnesium bromide (3M in Et2O, 0.3 mL, 0.9 mmol) and carbon dioxide were reacted in anhydrous
tetrahydrofuran to give the crude reaction product, which was purified by acid-base work-up to give 2-
(2,5-dimethylphenyl)propanoic acid and 3-(2,5-dimethylphenyl)propanoic acid as a colourless
amorphous solid (58 mg, 0.33 mmol, 47%, : 27:20). The isomers were separated by flash silica
chromatography (0.01:8:1 acetic acid:hexanes:ethyl acetate).
S22
When ethylmagnesium bromide was replaced with cyclopentylmagnesium bromide (2M in Et2O, 0.45 mL,
0.9 mmol), 2-(2,5-dimethylphenyl)propanoic acid and 3-(2,5-dimethylphenyl)propanoic acid were
produced as a colourless amorphous solid (97 mg, 0.55 mmol, 78%, : 14:64).
2-(2,5-Dimethylphenyl)propanoic acid: δH (400 MHz, CDCl3) 7.13-7.05 (m, 2H), 7.02-6.96 (m, 1H), 3.97 (q,
J= 7.2Hz, 1H), 2.35 (s, 3H), 2.32 (s, 3H), 1.49 (d, J= 7.2Hz, 3H). δC (100 MHz, CDCl3) 180.4, 138.1, 135.9,
132.7, 130.4, 127.9, 127.2, 41.0, 21.1, 19.1, 17.5. GC-MS [70-1] (M+, relative abundance): 6.73 min (178,
99%).
Data were in accordance with those previously reported in the literature.7
3-(2,5-Dimethylphenyl)propanoic acid: δH (400 MHz, CDCl3) 7.09-7.03 (m, 1H), 7.01-6.93 (m, 2H), 2.97-
2.90 (m, 2H), 2.69-2.61 (m, 2H), 2.31 (s, 3H), 2.30 (s, 3H). δC (100 MHz, CDCl3) 178178.9, 138.1, 135.6,
132.7, 130.3, 129.3, 127.2, 34.4, 28.0, 20.9, 18.7. GC-MS [70-1] (M+, relative abundance): 7.01 min (178,
96%). HRMS (ESI-) calculated for C11H13O2- 177.0921. Found 177.0927.
S23
Mechanistic investigations into the iron-catalyzed hydrometallation of alkenes
and isomerization of Grignard reagents
i) Deuterium quench
Styrene (80 L, 0.7 mmol) was added to a solution of iron(II) chloride (0.9 mg, 0.007 mmol) and 2,6-bis-
[1-(2,6-diisoprpylphenylimino)ethyl]pyridine 6 (3.4 mg, 0.007 mmol) in anhydrous tetrahydrofuran (5
mL) at room temperature. Ethylmagnesium bromide (0.3 mL, 3M in Et2O, 0.9 mmol) was added
dropwise over 10 minutes and the reaction stirred at room temperature under an atmosphere of
nitrogen for 1 hour. d4-Methanol was added and the reaction stirred for 30 minutes. Aqueous sulphate
buffer solution (10 mL) was added and the aqueous phase extracted with diethyl ether (3 x 20 mL). The
combined organic extracts were washed with H2O and brine, dried (MgSO4) and concentrated in vacuo
to give ethyl-1-d1-benzene. δH (400 MHz, CDCl3) 7.37-7.15 (m, 5H), 2.65 (qt, JHH = 7.6 Hz, JHD = 2.1Hz, 1H),
1.25 (dt, JHH = 7.6 Hz, JHD = 1.1 Hz, 3H). GC-MS [35-AJP] (M+, relative abundance): 3.11 min (107, 98%).
S24
ii) Experiment using d5-ethylmagnesium bromide
d5-Bromoethane (0.2 mL, 3 mmol) was added to magnesium turnings (650 mg, 27 mmol) in hot diethyl
ether (10 mL). A single iodine crystal was added to initiate the reaction, and the remaining d5-
bromoethane (1.8 mL, 24 mmol) was added dropwise at a rate to maintain reflux. The reaction was
stirred for a further 2 hours, allowed to settle, and the Grignard reagent siphoned off and stored in a
Young’s flask under an atmosphere of nitrogen. The concentration of the Grignard reagent was
determined to be 1.5M after titration against 2-hydroxybenzaldehyde phenylhydrazone.
Styrene (80 L, 0.7 mmol) was added to a solution of iron(II) chloride (0.9 mg, 0.007 mmol) and 2,6-bis-
[1-(2,6-diisoprpylphenylimino)ethyl]pyridine 6 (3.4 mg, 0.007 mmol) in anhydrous tetrahydrofuran (5
mL) at room temperature. d5-Ethylmagnesium bromide (0.6 mL, 1.5M in Et2O, 0.9 mmol) was added
dropwise over 10 minutes and the reaction stirred at room temperature under an atmosphere of
nitrogen for 1 hour. Carbon dioxide was bubbled through the reaction via a needle for 30 minutes.
Aqueous sulphate buffer solution (10 mL) was added and the aqueous phase extracted with diethyl
ether (3 x 20 mL). The combined organic extracts were washed with H2O and brine, dried (MgSO4) and
concentrated in vacuo to give a mixture of 4 products.
δH (400 MHz, CDCl3) 7.38-7.26 (m, 5H), 3.79-3.72 (m, 1H), 1.56-1.47 (m, 1.07H). GC-MS [70-1] (M+,
relative abundance): 5.75 min (153, 152, 151, 150, 92%).
2-Phenylpropanoic acid
δC (125 MHz, CDCl3) 181.1, 139.7, 128.6, 127.6, 127.3, 45.37, 18.03.
2-Phenyl-3-d1-propanoic acid
δC (125 MHz, CDCl3) 181.1, 139.7, 128.6, 127.6, 127.3, 45.30, 17.75 (t, JCD = 19.9 Hz)
2-Phenyl-3,3-d2-propanoic acid
δC (125 MHz, CDCl3) 181.1, 139.7, 128.6, 127.6, 127.3, 45.23, 17.48 (quintet, JCD = 19.8 Hz)
S25
2-Phenyl-3,3,3-d3-propanoic acid
δC (125 MHz, CDCl3) 181.1, 139.7, 128.6, 127.6, 127.3, 45.16, 17.36 (septet, JCD = 19.8 Hz)
S26
GC-MS [70-1] (M+, relative abundance): 5.75 min (153, 152, 151, 150, 92%)
iii) Preparation of phenethylmagnesium bromide and isomerization under reaction
conditions
(2-Bromoethyl)benzene (0.15 mL, 1 mmol) was added to magnesium turnings (300 mg, 12 mmol) in hot
diethyl ether (5 mL). A single iodine crystal was added to initiate the reaction, and the remaining (2-
bromoethyl)benzene (1.2 mL, 9 mmol) was added dropwise at a rate to maintain reflux. The reaction
was stirred for a further 2 hours, allowed to settle, and the Grignard reagent siphoned off and stored in
a Young’s flask under an atmosphere of nitrogen. The concentration of the Grignard reagent was
determined to be 1.4M after titration against 2-hydroxybenzaldehyde phenylhydrazone.
Control:
Phenethylmagnesium bromide 10 (0.7 mL, 1 mmol) was added to anhydrous tetrahydrofuran and
carbon dioxide was bubbled through the reaction for 30 minutes to give 3-phenylpropanoic acid 2 as
colourless needles (140 mg, 93%). δH (400 MHz, CDCl3) 7.35-7.28 (m, 2H), 7.26-7.20 (m, 2H), 3.01-2.95
(m, 2H), 3.74-3.68 (m, 2H). δC (100 MHz, CDCl3) 178.8, 140.1, 128.54, 128.3, 126.4, 35.5, 30.6.
S27
Isomerization experiment in the absence of tert-butylstyrene:
Phenethylmagnesium bromide 10 (0.7 mL, 1 mmol) was added to a solution of iron(II) chloride (0.9 mg,
0.007 mmol) and 2,6-bis-[1-(2,6-diisoprpylphenylimino)ethyl]pyridine 6 (3.4 mg, 0.007 mmol) in
anhydrous tetrahydrofuran (5 mL) at room temperature, and the reaction mixture stirred for 2 hours.
Carbon dioxide was bubbled through the reaction via a needle for 30 minutes. Aqueous sulphate buffer
solution (10 mL) was added and the aqueous phase extracted with diethyl ether (3 x 20 mL). The
combined organic extracts were washed with H2O and brine, dried (MgSO4) and concentrated in vacuo
to give a mixture of the crude products of the reaction. Trimethoxybenzene (33.6 mg, 0.2 mmol) was
added as an internal standard, and a yield for the reaction determined by 1H NMR.
Trimethoxybenzene (20 mol%): 6.85ppm (s, 3H); 2-Phenylpropionic acid: 1.53 (d, 3H); (1.26/3) × 20 = 8% Yield;
3-Phenylpropionic acid: 3.02-2.95 (m, 2H); (7.91/2) × 20 = 79% Yield
3% styrene and a similar quantity of ethylbenzene were also observed.
Addition of tert-butylstyrene:
Phenethylmagnesium bromide 10 (0.7 mL, 1 mmol) was added to a solution of iron(II) chloride (0.9 mg,
0.007 mmol) tert-butylstyrene (180 µL, 1 mmol) and 2,6-bis-[1-(2,6-diisoprpylphenylimino)ethyl]pyridine
6 (3.4 mg, 0.007 mmol) in anhydrous tetrahydrofuran (5 mL) at room temperature, and the reaction
mixture stirred for 2 hours. Carbon dioxide was bubbled through the reaction via a needle for 30
minutes. Aqueous sulphate buffer solution (10 mL) was added and the aqueous phase extracted with
diethyl ether (3 x 20 mL). The combined organic extracts were washed with H2O and brine, dried
(MgSO4) and concentrated in vacuo to give a mixture of the crude products of the reaction.
Trimethoxybenzene (33.6 mg, 0.2 mmol) was added as an internal standard, and a yield for the reaction
determined by 1H NMR.
S28
Trimethoxybenzene (20 mol%): 6.85ppm (s, 3H);
2-Phenylpropionic acid: 1.53 (d, 3H); (4.23/1.5) × 20 = 56% Yield; 3-Phenylpropionic acid: 3.02-2.95 (m, 2H);
((0.38+1.12-0.45+0.38)/2) × 20 = 14% Yield; Styrene: 5.26 (dd, 2H); (1.15/1) × 20 = 23% Yield.
2-(4-tert-Butylphenyl)propanoic acid: 1.52 (d, 3H); (1.68/1.5) × 20 = 22% Yield; 3-(4-tert-Butylphenyl)propionic
acid: 2.98-2.90 (m, 2H); ((0.45+1.16-0.38+0.45)/2) × 20 = 17% Yield; tert-Butylstyrene: 5.21 (dd, 2H); (2.63/1) × 20
= 53% Yield.
iv) Attempted preparation of (1-phenylethyl)magnesium bromide from (1-
bromoethyl)benzene
(1-Bromoethyl)benzene 11 (0.14 mL, 1 mmol) was added to magnesium turnings (150 mg, 6 mmol) in
hot tetrahydrofuran (5 mL). A single iodine crystal was added to initiate the reaction, and the remaining
(1-bromoethyl)benzene (0.54 mL, 4 mmol) was added dropwise at a rate to maintain reflux. The reaction
was allowed to settle, and a 1 mL (1 mmol) sample removed and added to a Schlenk tube containing
tetrahydrofuran (5 mL). Carbon dioxide was bubbled through the reaction for 30 minutes. Aqueous
sulphate buffer solution (10 mL) was added and the aqueous phase extracted with diethyl ether (3 x 20
mL). The combined organic extracts were washed with H2O and brine, dried (MgSO4) and concentrated
in vacuo to give a mixture of the crude products, which were analysed 1H NMR and by GC-MS.
Dimethoxybenzene (27.6 mg, 0.2 mmol) was added as an internal standard, and a yield for the reaction
determined for 1H NMR. A near quantitative conversion to 2,3-diphenylbutane 12 was observed, with no
formation of 2-phenylpropanoic acid 2.
S29
Dimethoxybenzene (20 mol%): 6.85ppm (s, 4H); (RR,SS)-2,3-diphenylbutane: 3.01-2.87 (m, 2H), 1.33-1.22 (m, 6H);
(2.39/2) × 20 = 24% Yield; (RS,RS)-2,3-diphenylbutane: 2.86-2.74 (m, 2H), 1.07-0.98 (m, 6H); (2.41/2) × 20 = 24%
Yield, therefore overall yield of 48% (of a possible 50% due to dimerization).
GC-MS [70-1] (M+, identity, rel. intensity): 4.35 min (138, dimethoxybenzene, n/a), 7.13 min (210, 2,3-
diphenylbutane, 50%), 7.24 min (210, 2,3-diphenylbutane, 50%).
v) Preliminary investigation of reaction rate with respect to reaction concentration
According to general procedure C, nine (three sets of three) parallel reactions were undertaken in 5, 10
and 20 mL of tetrahydrofuran. Within each set of 3 reactions, carbon dioxide was bubbled through the
reaction mixture after either 10, 20 or 30 minutes, and the yield of 2-phenylpropanoic acid determined
by 1H NMR (using dimethoxybenzene as an internal standard). The rate of reaction in 5 mL of THF was
found to be higher than in 10 mL, which was in turn higher than the rate of reaction in 20 mL. Although
the rates of reaction were not accurately measured, the initial rates appeared to be approximately first
order with respect to concentration, implying a homogeneous reaction mixture. Further, more detailed
investigations are currently being pursued.
% Yield after
THF volume/mL 10 min 20 min 30 min
5 33 45 57 10 26 34 41 20 19 26 30
S30
ICP Analysis
ICP-MS (Inductively Coupled Plasma-Mass Spectrometry) of the reaction mixture: A standard reaction mixture (FeCl2 (Strem Chemicals Inc. (UK); anhydrous iron chloride, 98% (product number 93-2631. Lot 19226800, 44.00000% Fe), bis(imino)pyridine ligand 6, ethylmagnesium bromide (3M in Et2O, Sigma Aldrich), THF) was evaporated to dryness, redissolved in 6 mL of HNO3 and diluted by a factor of 50 with Milli-Q water. Analysis was conducted on a Thermo-Finnigan Neptune multiple-collector inductively coupled plasma mass spectrometer (MC-ICP-MS) (Bristol Neptune 1, Serial No. 1002), using an SLSRS5 standard for calibration. The abundance of each metal in the sample was recorded relative to the abundance of iron.
Table S3. ICP-MS Analysis on the abundance (ppm) of elements in reaction mixture, relative to Fe
Ti Co Ni Cu Zr Ru Rh Pd Ag Ir Pt Au 560 570 60 130 210 <1 30 1060 <1 60 <1 10
Investigation of potential catalytic role of trace metal impurities
Fifteen parallel reactions (A-G) were undertaken to investigate if trace metal impurities present in the
iron salt used could have a role in the observed catalysis.13 Copper(II) chloride, nickel(II) acetylacetonate,
cobalt(II) chloride, bis(1,5-cyclooctadiene)diiridium(I) dichloride, bis(1,5-cyclooctadiene)rhodium(I)
tetrafluoroborate, tetrakis(triphenylphosphine)palladium(0) and ruthenium(III) chloride were used. The
metal complexes were added at a 1000 ppm concentration relative to iron, and reactions were
conducted in the presence and absence of iron to ascertain any beneficial effect of the trace metal salt
in isolation or in conjunction with iron.
Styrene (80µL, 0.7 mmol) was added to a solution of a metal complex (0.01 µmol) (+/- FeCl2 (0.9 mg,
0.007 mmol)) and (±)-(N,N’-bis(pyridin-2-ylmethylene)cyclohexane-1,2-diamine 5 (2.1 mg, 0.007 mmol)
in anhydrous tetrahydrofuran (5 mL) at room temperature. Ethylmagnesium bromide (0.3 mL, 3M in
Et2O, 0.9 mmol) was added dropwise over 10 minutes and the reaction stirred at room temperature
under an atmosphere of nitrogen for 1 hour. Carbon dioxide was bubbled through the reaction via a
needle for 30 minutes. Sulphate buffer solution (10 mL) was added and the aqueous phase extracted
with diethyl ether (3 x 20 mL). The combined organic extracts were washed with H2O and brine, dried
(MgSO4) and concentrated in vacuo to give the crude reaction products. Dimethoxybenzene (19.3 mg,
0.14 mmol) was added as an internal standard, and a yield for the reaction determined for 1H NMR.
Table S4. Addition of trace metal quantities to standard reaction
Reaction FeCl2 /mol% Ligand 5/mol% Metal salt (1000ppm) %Yield of 2-Phenylpropanoic acid
Control 1 1 - 80
A 1 1 CuCl2 79
A’ - 1 CuCl2 0
B 1 1 Ni(acac)2 74
B’ - 1 Ni(acac)2 0
C 1 1 CoCl2 80
C’ - 1 CoCl2 0
D 1 1 Ir2Cl2(COD)2 78
S31
D’ - 1 Ir2Cl2(COD)2 0
E 1 1 Rh(COD)2.BF4 76
E’ - 1 Rh(COD)2.BF4 0
F 1 1 Pd(Ph3)4 78
F’ - 1 Pd(Ph3)4 0
G 1 1 RuCl3 75
G’ - 1 RuCl3 0
The addition of metal salts of Cu, Ni, Co, Ir, Rh, Pd, and Ru to the reaction did not increase the yield of 2-
phenylpropanoic acid, and in the absence of iron, no catalytic activity was observed for any of the metal
salts added.
S32
NMR traces of compounds 5, 6, 7e-f, 2, 8a-l
(±)-(N,N’-Bis(pyridin-2-ylmethylene)cyclohexane-1,2-diamine 5
300 MHz
100 MHz
S33
2,6-Bis-[1-(2,6-diisopropylphenylimino)ethyl]pyridine 6
400 MHz
125 MHz
S34
4-iso-Butylstyrene 7e
400 MHz
100 MHz
S35
3-Benzyloxystyrene 7f
400 MHz
100 MHz
S36
2-Methoxystyrene 8g
400 MHz
100 MHZ
S37
3-Methoxystyrene 8h
400 MHz
100 MHz
S38
2,5-Dimethoxystyrene 8j
400 MHz
100 MHz
S39
2-Phenylpropanoic acid 2
400 MHz
100 MHz
S40
3-Phenylpropanoic acid 2
400 MHz
100 MHz
S41
2-(4-Methylphenyl)propanoic acid 8a
300 MHz
75 MHz
S42
2-(3-Methylphenyl)propanoic acid 8b
400 MHz
100 MHz
S43
2-(2-Methylphenyl)propanoic acid 8c
500 MHz
125 MHz
S44
2-(4-tert-Butylphenyl)propanoic acid 8d
400 MHz
100 MHz
S45
2-(4-iso-Butylphenyl)propanoic acid 8e
500 MHz
125 MHz
S46
2-(3-(Benzyloxy)phenyl)propanoic acid 8f
500 MHz
125 MHz
S47
2-(2-Methoxyphenyl)propanoic acid 8g
400 MHz
100 MHz
S48
2-(3-Methoxyphenyl)propanoic acid 8h
400 MHz
100 MHz
S49
2-(4-Methoxyphenyl)propanoic acid 8i
300 MHz
75 MHz
S50
2-(2,5-Dimethoxyphenyl)propanoic acid 8j
400 MHz
100 MHz
S51
2-(3,4-Dimethoxyphenyl)propanoic acid 8k
500 MHz
125 MHz
S52
2-(2-biphenyl)propanoic acid 8l
500 MHz
125 MHz
S53
2-(4-Fluorophenyl)propanoic acid 8m
500 MHz
125 MHz
S54
470 MHz
S55
2-(2,4-Dimethylphenyl)propanoic acid 8n
400 MHz
100 MHz
S56
3-(2,4-Dimethylphenyl)propanoic acid 8n
400 MHz
100 MHz
S57
2-(2,5-Dimethylphenyl)propanoic acid 8o
400 MHz
100 MHz
S58
3-(2,5-Dimethylphenyl)propanoic acid 8o
400 MHz
100 MHz
S59
GC-MS traces of compounds 2, 8a-l
2-Phenylpropanoic acid 2
2-(4-Methylphenyl)propanoic acid 8a
S60
2-(3-Methylphenyl)propanoic acid 8b
2-(2-Methylphenyl)propanoic acid 8c
S61
2-(4-tert-Butylphenyl)propanoic acid 8d
2-(4-iso-Butylphenyl)propanoic acid 8e
S62
2-(2-Methoxyphenyl)propanoic acid 8g
2-(3-Methoxyphenyl)propanoic acid 8h
S63
2-(4-Methoxyphenyl)propanoic acid 8i
2-(2,5-Dimethoxyphenyl)propanoic acid 8j
S64
2-(3,4-Dimethoxyphenyl)propanoic acid 8k
2-(2-biphenyl)propanoic acid 8l
S65
2-(4-Fluorophenyl)propanoic acid 8m
2-(2,4-Dimethylphenyl)propanoic acid 8n
S66
3-(2,4-Dimethylphenyl)propanoic acid 8n
2-(2,5-Dimethylphenyl)propanoic acid 8o
S67
3-(2,5-Dimethylphenyl)propanoic acid 8o
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