Inter- and Intramolecular Hydroacylation of Alkenes employing a Novel Bifunctional Catalyst System

48 Pages·2011·1.1 MB·English

Electronic Supplementary Material (ESI) for Chemical Communications
This journal is © The Royal Society of Chemistry 2011

Supporting Information for

Inter- and Intramolecular Hydroacylation of Alkenes
employing a Novel Bifunctional Catalyst System

Nicolas R. Vautravers, Damien D. Regent, and Bernhard Breit*

Institute fűr Organische Chemie und Biochemie, Albert-Ludwigs-Universität Freiburg,
Albertstrasse 21,
79104, Freiburg, Germany

Table of contents

General considerations S-2

General procedure for hydroacylation reactions S-2

Characterization data

- Ligand L S-2
- Substrates S-5
- Products S-12

References S-17

1H NMR and 13C NMR spectra of isolated compounds S-18

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General considerations

All reactions were carried out in oven-dried glasswares under an argon atmosphere (Argon
5.0 from Sauerstoffwerke Friedrichshafen) using standard Schlenk techniques. All reagents
were purchased from commercial sources and used as received. All solvents were dried and
distilled by standard procedures. Chromatographic purification of products was accomplished
using Machery-Nagel silica gel 60® (230-400 mesh).
Nuclear magnetic resonance spectra were acquired on a Bruker Avance 400 spectrometer
(400 MHz, 162.0 MHz and 100.6 MHz for 1H, 31P and 13C respectively) and on a Varian
Mercury (300 MHz, 121.5 MHz and 75.5 MHz for 1H, 31P and 13C respectively). All 1H NMR
spectra are reported in parts per million (ppm) downfield of TMS and were measured relative
to the signals at 7.26 ppm (CHCl ) and 2.50 ppm (d -DMSO). All 13C NMR spectra were
3 6
reported in ppm relative to residual CHCl (77.16 ppm) and d -DMSO (39.52 ppm) and were
3 6
obtained with 1H decoupling. 31P NMR spectrum was referenced to external 85 % H PO .
3 4
Data for 1H NMR are described as follow: chemical shift (δ in ppm), multiplicity (s, singlet;
d, doublet; t, triplet; q, quartet; quint, quintuplet; m, multiplet; br, broad signal), coupling
constant (Hz), integration. Data for 13C NMR and 31P NMR spectra are described in terms of
chemical shift (δ in ppm). High resolution mass spectra were obtained on a Finnigan MAT
8200 instrument (EI: 70 eV; CI/NH : 110 eV). Elementary analysis were performed on an
3
Elementar vario (Fa. Elementar Analysensysteme GmbH).
2-amino-6-picoline, 2-amino-3-picoline, N-bromosuccinimide (Fluorochem), 2,6-di-tert-
butylcresol, allyl benzene, styrene, 4-vinyl-1-cyclohexene (Acros), o-bromostyrene, 3-bromo-
4-methylaniline, 4-bromo-3-methylbenzoic acid methyl ester, 2-bromo-4-
methylbenzaldehyde, 5-hexen-1-ol, 5-hexenoic acid (AlfaAesar), potassium
vinyltrifluoroborate, 2-bromo-4-nitrotoluene, 2-bromopyridine, 2-bromo-5-
fluorobenzaldehyde, 2-bromo-5-hydroxybenzaldehyde, benzaldehyde, p-chlorobenzaldehyde,
p-methoxybenzaldehyde, biphenyl-4-carboxaldehyde, methyl acrylate, 1-octene,
tributyl(vinyl)tin, [Rh(COD)Cl] , [Rh(CO) Cl] , [Pd(PPh ) ], [CoCl .6H O] (Sigma Aldrich),
2 2 2 3 4 2 2
[PdCl ] (Merck), 2-bromo-5-chlorotoluene, 1-bromo-2-methylnaphthalene (ABCR), 6-
2
bromoveratraldehyde, ethyl 4-piperidinecarboxylate (ChemPur) were purchased commercially
and used as received. [Rh(COD) BF ] and [Rh(COD)acac] was generously given by Umicore.
2 4
Diphenyl(2-pyridyl)phosphine (L´) was made according to literature procedure.1

General procedure for hydroacylation reactions

GP1

[Rh(COD)Cl] (5mol%)
2
O L (10 mol%) O
R +
1 R H R R
2 Toluene (c = 1.1 M) 1 2
150 °C, 24 h.

A mixture of substituted benzaldehyde (0.22 mmol), ligand L (0.022 mmol, 6.8 mg) and
[Rh(COD)Cl] (0.011 mmol, 5.4 mg) was dissolved in toluene (200 μL) in a 8 mL closed
2
Schlenk tube and magnetically stirred for 24 hours at 150 °C. The solution was concentrated
to give a residue that was purified by silica gel column chromatography (eluting with
Petroleum Ether/ CH Cl = 2/1).
2 2

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GP2
O [Rh(COD)2]BF4 (5 mol%) O
L (5 mol%)
H
Toluene (c = 1.1 M)
R R
150 °C, 1h.

A mixture of substituted o-vinylbenzaldehyde (0.22 mmol), ligand L (0.011 mmol, 3.4 mg)
and [Rh(COD) ]BF (0.011 mmol, 4.5 mg) was dissolved in toluene (200 μL) in a 8 mL
2 4
closed Schlenk tube and magnetically stirred for 1 hour at 150 °C. The solution was
concentrated to give a residue that was purified by silica gel column chromatography (eluting
with CH Cl ).
2 2

Characterization data

Ligand L

6-methyl-2-(pivaloylamino)-pyridine (1)2

A solution of trimethylacetylchloride (12.51 mL, 101.7 mmol) in DCM
O
(15 mL) was slowly added to an ice-cooled solution of 2-amino-6-
N N picoline (10 g, 92.5 mmol) and NEt (16.11 mL, 115.6 mmol) in DCM
H 3
(200 mL). The reaction mixture was stirred at 0 °C for 15 minutes and
overnight at room temperature. It was then poured into water (150 mL) and extracted with
DCM (3 x 60 mL). The organic phase was washed with dilute NaHCO (60 mL), dried over
3
MgSO and concentrated in vacuo. The residue was recrystallized from pentane leaving 6-
4
methyl-2-(pivaloylamino)-pyridine (1) as white crystals (17.7 g, 92.0 mmol, 99%).
1H NMR (400.13 MHz, CDCl ): δ= 1.33 (s, 9H), 2.45 (s, 3H), 6.88 (bd, J = 7.5 Hz, 1H), 7.58
3
(dd, J = 8.2 Hz, J = 7.5 Hz, 1H), 7.96 (bs, 1H), 8.05 (d, J = 8.2 Hz, 1H); 13C{1H} NMR
(100.6 MHz, CDCl ): δ = 24.1, 27.6, 39.9, 110.9, 119.2, 138.8, 151.1, 154.8, 177.2. LRMS
3
(CI): Calcd. for C H N O (M+H): 193.3; Found: 193.2. Elemental analysis for C H N O:
11 17 2 11 16 2
C, 68.72; H, 8.39; N, 14.57. Found: C, 68.76; H, 8.55; N, 14.44.

3,6-dimethyl-2-(pivaloylamino)-pyridine (2)

O n-BuLi (2.5 M in hexanes, 34.4 mL, 85.9 mmol) was added dropwise at -
78 °C to a solution of 6-methyl-2-(pivaloylamino)-pyridine (1) (7.5 g, 39
N N
mmol) in 100 mL of THF. The resulting orange solution was stirred at
H
this temperature for 30 minutes before being stirred at 0 °C for one
further hour. Methyl iodide (2.68 mL, 43 mmol) was then slowly added to the ice-cooled
solution and the reaction mixture was allowed to warm to room temperature overnight. The
mixture was then poured into water, and extracted three times with Et O (3 x 30 mL). The
2
combined organic layers were washed with brine, dried over MgSO and evaporated to
4
dryness. The crude was purified by silica gel column chromatography (eluting with
Cyclohexane/EtOAc, 70/30) yielding 3,6-dimethyl-2-(pivaloylamino)-pyridine (2) as white
crystals (5.2 g, 28.9 mmol, 74%).
1H NMR (400.13 MHz, CDCl ): δ= 1.34 (s, 9H), 2.17 (s, 3H), 2.46 (s, 3H), 6.95 (d, J = 7.8
3
Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.72 (bs, 1H); 13C{1H} NMR (100.6 MHz, CDCl ): δ =
3
17.9, 23.7, 27.8, 39.5, 121.6, 126.1, 140.3, 148.7, 154.7, 176.9; HRMS (EI): Calcd. for
C H N O (M): 206.1419; Found: 206.1423. Elemental analysis for C H N O: C, 69.87;
12 18 2 12 18 2
H, 8.79; N, 13.58. Found: C, 69.57; H, 8.91; N, 13.35.
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3-methyl-2-(pivaloylamino)-6-(trimethylsilylmethyl)-pyridine (3)

O n-BuLi (2.5 M in hexanes, 9.4 mL, 23.5 mmol) wad slowly added at -
78 °C to a mixture of KOtBu (2.6 g, 23.2 mmol), DIPA (3.19 mL,
N N
22.6 mmol) and anhydrous THF (25 mL). It was stirred at this
H
Si temperature for 30 minutes before a solution of 3,6-dimethyl-2-
(pivaloylamino)-pyridine (2) (2.06 g, 10.0 mmol) in THF (170 mL)
being slowly canuled in and reacted for a further hour at -78 °C. The red mixture was
subsequently quenched with a solution of TMSCl (16 mmol, 2.1 mL) in THF (5 mL) and
stirred overnight at room temperature. After hydrolysis (30 mL H O), DCM extraction (3 x 30
2
mL) and drying (MgSO ), the solvent was removed in vacuo and the crude was purified by
4
column chromatography on silica gel (eluting with Cyclohexane/EtOAc, 70/30) affording 3-
methyl-2-(pivaloylamino)-6-(trimethylsilylmethyl)-pyridine (3) as white crystals (2.00 g, 7.22
mmol, 72%).
1H NMR (400.13 MHz, CDCl ): δ= 0.01 (s, 9H), 1.34 (s, 9H), 2.14 (s, 3H), 2.24 (s, 2H), 6.78
3
(d, J = 7.8 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.55 (bs, 1H); 13C{1H} NMR (100.6 MHz,
CDCl ): δ= -1.5, 17.9, 27.8, 29.3, 39.5, 120.5, 124.1, 140.1, 148.5, 157.7, 176.7. HRMS (EI):
3
Calcd. for C H ON Si (M): 278.1814; Found: 278.1814. Elemental analysis for
15 26 2
C H N OSi: C, 64.70; H, 9.41; N, 10.06. Found: C, 64.50; H, 9.57; N, 9.85.
15 26 2

6-chloromethyl-3-methyl-2-(pivaloylamino)-pyridine (4)

O Dry CsF (1.1 g, 7.2 mmol) was added at 25 °C to a solution of 3-methyl-
2-(pivaloylamino)-6-(trimethylsilylmethyl)-pyridine (3) (0.5 g, 1.8
N N
mmol) and C Cl (1.7 g, 7.2 mmol) in CH CN (30 mL). The
H 2 6 3
Cl heterogeneous solution was stirred at 60 °C for 5 hours. After cooling to
25 °C, the mixture was poured into a separatory funnel containing EtOAc (45 mL) and H O
2
(45 mL) and was extracted with EtOAc (3 x 45 mL). The combined organic fractions were
washed with brine (70 mL) and dried over MgSO and concentrated in vacuo to give pure 6-
4
chloromethyl-3-methyl-2-(pivaloylamino)-pyridine (4) as a yellowish solid (0.38 g, 88%).
1H NMR (400.13 MHz, CDCl ): δ= 1.35 (s, 9H), 2.22 (s, 3H), 4.57 (s, 2H), 7.26 (d, J = 7.7
3
Hz, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.70 (bs, 1H); 13C{1H} NMR (100.6 MHz, CDCl ): δ =
3
18.2, 27.7, 39.6, 46.3, 121.1, 129.1, 141.0, 149.2, 152.9, 177.0. HRMS (EI): Calcd. for
C H ON Cl (M): 240.1029; Found: 240.1031.
12 17 2

6-chloromethyl-3-methyl-2-aminopyridine (5)

A solution of 6-chloromethyl-3-methyl-2-(pivaloylamino)-pyridine (4) (0.38
g, 1.58 mmol) was dissolved in a concentrated HCl solution (5 mL) and
N NH
2 refluxed overnight. After cooling to room temperature, the mixture was
Cl neutralized with K CO and extracted with DCM (3 x 20 mL). The combined
2 3
organic fractions were dried over MgSO , filtered and concentrated in vacuo. The crude was
4
purified by flash chromatography on silica gel (Cyclohexane/EtOAc, 70/30) affording 6-
chloromethyl-3-methyl-2-aminopyridine (5) as white crystals (0.18 g, 1.15 mmol, 72%). The
product has to be stored at -20 °C to avoid any polymerisation.
1H NMR (400.13 MHz, CDCl ): δ= 2.12 (s, 3H), 4.47 (s, 2H), 4.50 (br s, 2H), 6.73 (d, J =
3
7.4 Hz, 1H), 7.27 (br d, J = 7.4 Hz, 1H); 13C{1H} NMR (100.6 MHz, CDCl ): δ= 17.0, 47.0,
3
113.5, 116.5, 138.6, 152.5, 157.0. LRMS (EI): Calcd. for C H N Cl (M): 156.6; Found:
7 9 2
157.0. Elemental analysis for C H ClN : C, 53.68; H, 5.79; N, 17.89. Found: C, 53.69; H,
7 9 2
5.95; N, 17.72.

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6-diphenylphosphinomethyl-3-methyl-2-aminopyridine L

Na (236.2 mg, 9.84 mmol) was added over 10 min to liquid ammonia (30
mL) at -78 °C. The dark blue solution was stirred at this temperature for 20
N NH2 minutes and then treated portionwise with PPh (1.29 g, 4.92 mmol) over 5
3
PPh2 minutes. The dark red-orange solution was stirred for a further 2 hours at -78
°C before the addition of 6-chloromethyl-3-methyl-2-aminopyridine (5) (770 mg, 4.78 mmol).
THF (30 mL) was then added after 40 minutes and the cooling bath removed. Ammonia was
allowed to evaporate overnight and the residue was quenched with H O (10 mL), extracted
2
with Et O (3 x 8 mL) and dried over Na SO . The solvent was evaporated in vacuo, and
2 2 4
subsequent flash column chromatography on silica gel (DCM, then DCM/EtOAc, 10/3)
afforded ligand L, 6-diphenylphosphinomethyl-3-methyl-2-aminopyridine, as a white solid
(1.2 g, 3.9 mmol, 80%).
1H NMR (400.13 MHz, CDCl ): δ= 2.05 (s, 3H), 3.44 (s, 2H), 4.38 (br s, 2H), 6.29 (dd, J =
3
7.4 Hz, J = 1.5 Hz, 1H), 7.06 (d, J = 7.4 Hz, 1H), 7.31 (m, 6H), 7.44 (m, 4H); 13C{1H} NMR
(100.6 MHz, CDCl ): 16.8, 38.1 (d, J = 14.9 Hz), 113.8 (d, J = 2.7 Hz), 114.3 (d, J = 6.7 Hz),
3
128.4 (d, J = 6.7 Hz), 128.7, 133.1 (d, J = 18.7 Hz), 138.3, 138.8 (d, J = 15.3 Hz), 153.7 (d, J
= 8.0 Hz), 156.6; 31P{1H} NMR (101.3 MHz, CDCl ) δ = -12.1; HRMS (EI): Calcd. for
3
C H N P (M): 306.1286; Found: 306.1286. Elemental analysis for C H N P: C, 74.49; H,
19 19 2 19 19 2
6.25; N, 9.14. Found: C, 74.39; H, 6.15; N, 9.21.

Substrates

o-vinylbenzaldehyde3

O n-BuLi (2.5 M solution in hexanes, 4.82 mL, 12.03 mmol) was slowly added to a
solution of o-bromostyrene (2 g, 1.37 mL, 10.93 mmol) in THF (40 mL) at -78
°C and stirred for 1 hour at this temperature. DMF (1.02 mL, 13.12 mmol) was
then added dropwise to the suspension and the mixture stirred for a further 20
min. Saturated aqueous NH Cl (40 mL) was added and the mixture was extracted with Et O
4 2
(3 x 30 mL). The combined organic extracts were dried over MgSO and concentrated in
4
vacuo. The residue was purified by silica gel column chromatography (eluting with a gradient
of Cyclohexane/EtOAc, 50:1 to 20:1) to afford o-vinylbenzaldehyde as a colorless oil (1.08 g,
8.17 mmol, 75%).
1H NMR (300.07 MHz, CDCl ) δ= 5.48 (d, J = 11.0 Hz, 1H), 5.70 (d, J = 17.3 Hz, 1H), 7.43
3
(m, 1H), 7.52 (dd, J = 17.3 Hz, J = 11.0 Hz, 1H), 7.52 (m, 2H), 7.82 (d, J = 7.7 Hz, 1H),
10.29 (s, 1H); 13C{1H} NMR (100.6 MHz, CDCl ) δ = 119.5, 127.6, 128.0, 131.3, 133.0,
3
133.5, 133.9, 140.6, 192.5. HRMS (EI): Calcd. for C H O (M): 132.0575; Found: 132.0576.
9 8

2-methyl-5-phthalimido-bromobenzene

O A mixture of 3-bromo-4-methylaniline (3.0 g, 16.1 mmol) and
phthalic anhydride (2.38 g, 16.1 mmol) were stirred and held at 190
N
°C for 1 hour. After cooling to room temperature, the residue was
purified by silica gel chromatography (eluting with EtOAc) to yield
O Br
2-methyl-5-phthalimido-bromobenzene as a white crystalline solid (5
g, 15.8 mmol, 98%).
1H NMR (400.13 MHz, CDCl ) δ = 2.45 (s, 3H), 7.31 (dd, J = 8.1 Hz, J = 2.1 Hz, 1H), 7.37
3
(br d, J = 8.1 Hz, 1H), 7.65 (d, J = 2.1 Hz, 1H), 7.80 (m, 2H), 7.95 (m, 2H); 13C{1H} NMR
(100.6 MHz, CDCl ) δ = 22.8, 124.0, 124.9, 125.5, 130.4, 130.5, 131.1, 131.8, 134.7, 138.2,
3
167.1. HRMS (EI): Calcd. for C H O NBr (M): 314.9895; Found: 314.9888.
15 10 2
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2-dibromomethyl-5-phthalimido-bromobenzene

O A mixture of 2-methyl-5-phthalimido-bromobenzene (2.75 g, 8.7
Br mmol), N-bromosuccinimide (4.64 g, 26.1 mmol) and AIBN (50
N mg) in anhydrous benzene (30 mL) was stirred and held at reflux
Br
for 16 hours. (AIBN (50 mg) was added every 3 hours) After
O Br
cooling to room temperature, the solvent was removed in vacuo
and the crude product was purified by silica gel chromatography (eluting with CH Cl ) to
2 2
yield 2-dibromomethyl-5-phthalimido-bromobenzene as a white solid (2.79 g, 5.89 mmol,
68%).
1H NMR (400.13 MHz, CDCl ) δ = 7.10 (s, 1H), 7.60 (dd, J = 2.1 Hz, J = 8.6 Hz, 1H), 7.70
3
(d, J = 2.1 Hz, 1H), 7.83 (m, 2H), 7.98 (m, 2H), 8.15 (d, J = 8.6 Hz, 1H); 13C{1H} NMR
(100.6 MHz, CDCl ) δ = 38.9, 119.8, 124.2, 126.2, 129.7, 131.5, 131.6, 133.8, 134.9, 139.8,
3
166.7. HRMS (EI): Calcd. for C H O NBr (M-Br): 391.8922; Found: 391.8914.
15 8 2 2

2-bromo-4-phthalimidobenzaldehyde

O 2-dibromomethyl-5-phthalimido-bromobenzene (2.2 g, 4.64 mmol)
O in H SO (20 mL) was stirred for 1 hour at room temperature.
2 4
N
EtOAc (20 mL) was added and the aqueous phase was extracted
with EtOAc (3 x 20 mL). The combined organic layers were
O Br
washed with water (20 mL) and brine (20 mL) and dried over
MgSO . After evaporation of the solvent, the crude product was purified by silica gel
4
chromatography (eluting with CH Cl ) to yield 2-bromo-4-phthalimidobenzaldehyde as a
2 2
white solid (1.2 g, 3.63 mmol, 78%).
1H NMR (400.13 MHz, CDCl ) δ = 7.67 (ddd, J = 8.4 Hz, J = 1.9 Hz, J = 0.8 Hz, 1H), 7.84
3
(m, 2H), 7.92 (d, J = 1.9 Hz, 1H), 7.99 (m, 2H), 8.05 (d, J = 8.4 Hz, 1H), 10.40 (d, J = 0.8
Hz, 1H); 13C{1H} NMR (100.6 MHz, CDCl ) δ = 124.3, 125.2, 127.1, 130.3, 130.8, 131.5,
3
132.4, 135.2, 137.8, 166.5, 191.2. HRMS (EI): Calcd. for C H O NBr (M): 328.9688;
15 8 3
Found: 328.9687.

4-phthalimido-2-vinylbenzaldehyde

O A solution of 2-bromo-4-phthalimidobenzaldehyde (0.492 g, 1.5
O mmol), potassium vinyltrifluoroborate (0.20 g, 1.5 mmol), PdCl
2
N
(5.3 mg, 0.03 mmol), PPh (23.5 mg, 0.09 mmol) and Cs CO (1.5
3 2 3
g, 4.5 mmol) in THF/H O (9/1) (3 mL) was heated at 85 °C for 22
2
O
hours under an argon atmosphere in a sealed tube. After cooling to
room temperature, H O (3 mL) was added, followed by extraction with CH Cl (3 x 10 mL).
2 2 2
The solvent was removed in vacuo and the crude product was purified by silica gel
chromatography (eluting with CH Cl ) to yield 4-phthalimido-2-vinylbenzaldehyde as a pale
2 2
yellow solid (0.334 g, 1.2 mmol, 81%).
1H NMR (400.13 MHz, CDCl ) δ = 5.58 (dd, J = 11.1 Hz, J = 1.0 Hz, 1H), 5.77 (dd, J = 17.4
3
Hz, J = 1.0 Hz; 1H), 7.57 (dd, J = 17.4 Hz, J = 11.1 Hz, 1H), 7.61 (dd, J = 8.1 Hz, J = 1.8 Hz,
1H), 7.74 (d, J = 1.8 Hz, 1H), 7.84 (m, 2H), 7.98 (m, 3H), 10.32 (s, 1H); 13C{1H} NMR
(100.6 MHz, CDCl ) δ = 120.7, 124.2, 125.0, 125.4, 131.7, 131.9, 132.1, 132.8, 134.9, 136.7,
3
141.7, 166.8, 191.4. HRMS (EI): Calcd. for C H O N (M): 277.0739; Found: 277.0737.
17 11 3

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2-bromo-1-dibromomethyl-4-nitrobenzene

O2N Br A mixture of 2-bromo-4-nitrotoluene (15.0 g, 69.4 mmol), N-
bromosuccinimide (37.0 g, 208.3 mmol) and AIBN (50 mg) in anhydrous
Br
benzene (200 mL) was stirred and held at reflux for 16 hours. (AIBN (50
Br mg) was added every 3 hours) After cooling to room temperature, the
solvent was removed in vacuo and the crude product was purified by silica gel
chromatography (eluting with CH Cl ) to yield 2-bromo-1-dibromomethyl-4-nitrobenzene as
2 2
a pale yellow solid (7.1 g, 19.0 mmol, 27%).
1H NMR (400.13 MHz, CDCl ) δ = 7.05 (s, 1H), 8.20 (d, J = 8.6 Hz, 1H), 8.31 (dd, J = 8.6
3
Hz, J = 2.2 Hz, 1H), 8.40 (d, J = 2.2 Hz, 1H); 13C{1H} NMR (100.6 MHz, CDCl ) δ = 37.4,
3
120.1, 123.4, 128.0, 132.2, 146.7, 148.2. HRMS (EI): Calcd. for C H O NBr (M-Br):
7 4 3 2
291.8609; Found: 291.8608.

2-bromo-4-nitrobenzaldehyde4

O N Br 2-bromo-1-dibromomethyl-4-nitrobenzene (7.1 g, 19.0 mmol) in H SO (70
2 2 4
mL) was heated for 3 hours at 60 °C. EtOAc (70 mL) was added and the
aqueous phase was extracted with EtOAc (3 x 70 mL). The combined
O organic layers were washed with water (70 mL) and brine (70 mL) and dried
over MgSO . After evaporation of the solvent, the crude product was purified by silica gel
4
chromatography (eluting with CH Cl ) to yield 2-bromo-4-nitrobenzaldehyde as a white solid
2 2
(4.2 g, 18.2 mmol, 96%).
1H NMR (400.13 MHz, CDCl ) δ = 8.08 (d, J = 8.6 Hz, 1H), 8.27 (ddd, J = 8.6 Hz, J = 2.1
3
Hz, J = 0.8 Hz, 1H), 8.53 (d, J = 2.1 Hz, J = 2.2 Hz, 1H), 10.40 (d, J = 0.8 Hz, 1H); 13C{1H}
NMR (100.6 MHz, CDCl ) δ = 122.9, 126.9, 129.2, 130.9, 137.5, 151.1, 190.1. HRMS (EI):
3
Calcd. for C H O NBr (M): 228.9375; Found: 228.9374.
7 4 3

4-nitro-2-vinylbenzaldehyde

O N A solution of 2-bromo-4-nitrobenzaldehyde (0.343 g, 1.5 mmol),
2
potassium vinyltrifluoroborate (0.20 g, 1.5 mmol), PdCl (5.3 mg, 0.03
2
mmol), PPh (23.5 mg, 0.09 mmol) and Cs CO (1.5 g, 4.5 mmol) in
3 2 3
O THF/H O (9/1) (3 mL) was heated at 85 °C for 22 hours under an argon
2
atmosphere in a sealed tube. After cooling to room temperature, H O (3 mL) was added,
2
followed by extraction with CH Cl (3 x 10 mL). The solvent was removed in vacuo and the
2 2
crude product was purified by silica gel chromatography (eluting with CH Cl ) to yield 4-
2 2
nitro-2-vinylbenzaldehyde as a pale yellow solid (0.193 g, 1.1 mmol, 73%).
1H NMR (400.13 MHz, CDCl ) δ = 5.71 (d, J = 11.1 Hz, 1H), 5.88 (d, J = 17.7 Hz, 1H), 7.51
3
(dd, J = 17.7 Hz, J = 11.1 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 8.23 (dd, J = 8.5 Hz, J = 2.2 Hz,
1H), 8.41 (d, J = 2.2 Hz, 1H), 10.40 (s, 1H); 13C{1H} NMR (100.6 MHz, CDCl ) δ = 122.4,
3
122.5, 122.7, 131.4, 132.0, 136.5, 142.0, 150.8, 190.5. HRMS (EI): Calcd. for C H O N (M):
9 7 3
177.0426; Found: 177.0428.

4-bromo-3-diacetoxymethylbenzoic acid methyl ester5

Br CrO (6.0 g, 60 mmol) was added in portions over 30 minutes to an
3
ice-cooled solution of 4-bromo-3-methylbenzoic acid methyl ester
O OAc
(4.60 g, 20.1 mmol) in AcOH (33 mL) and Ac O (34 mL) containing
2
O OAc H SO (5 mL). The mixture was stirred for another hour as the ice-
2 4
bath expired and then poured onto chilled water (300 mL). After 40 minutes of vigorous
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stirring, the white precipitate was filtrated and washed with water (3 x 20 mL) yielding 4-
bromo-3-diacetoxymethylbenzoic acid methyl ester as a white precipitate (5.7 g, 16.5 mmol,
82%).

1H NMR (400.13 MHz, CDCl ) δ = 2.16 (s, 6H), 3.94 (s, 3H), 7.68 (d, J = 8.3 Hz, 1H), 7.90
3
(dd, J = 8.3 Hz, J = 2.1 Hz, 1H), 7.92 (s, 1H), 8.2 (d, J = 2.1 Hz, 1H); 13C{1H} NMR (100.6
MHz, CDCl ) δ = 20.7, 52.4, 88.6, 127.8, 129.1, 129.8, 131.7, 133.5, 135.5, 165.8, 168.3.
3

4-bromo-3-formylbenzoic acid methyl ester5

Br 4-bromo-3-diacetoxymethylbenzoic acid methyl ester (5.7 g, 16.5 mmol)
was heated at reflux in a solution of MeOH/H O (1/1, 50 mL) containing
2
O
H SO for 1 hour. After cooling to room temperature, the solution was
2 4
O O diluted with H2O (120 mL) and extracted with EtOAc (3 x 30 mL). The
combined extracts were washed with H O (30 mL) and brine (30 mL), then dried over
2
MgSO . The solvent was removed in vacuo giving a pale yellow oil, which was refluxed for 3
4
hours in a solution of THF (40 mL) and 1N HCl (10 mL). THF was removed in vacuo and 4-
bromo-3-formylbenzoic acid methyl ester isolated as above as a pale yellow solid (3.1 g, 12.8
mmol, 77%).
1H NMR (300.07 MHz, CDCl ) δ = 3.94 (s, 3H), 7.75 (d, J = 8.3 Hz, 1H), 8.09 (dd, J = 8.3
3
Hz, J = 2.2 Hz, 1H), 8.53 (d, J = 2.2 Hz, 1H), 10.38 (s, 1H); 13C{1H} NMR (100.6 MHz,
CDCl ) δ = 52.7, 130.4, 131.1, 131.7, 133.7, 134.4, 135.6, 165.5, 190.9. HRMS (EI): Calcd.
3
for C H O Br (M): 241.9579; Found: 241.9574.
9 7 3

3-formyl-4-vinylbenzoic acid methyl ester

A solution of 4-bromo-3-formylbenzoic acid methyl ester (0.542 g, 2.24
mmol), potassium vinyltrifluoroborate (0.30 g, 2.24 mmol), PdCl (8.0 mg,
2
0.045 mmol), PPh (35.0 mg, 0.135 mmol) and Cs CO (2.19 g, 6.72 mmol)
O 3 2 3
in THF/H O (9/1) (5 mL) was heated at 85 °C for 22 hours under an argon
2
O O atmosphere in a sealed tube. After cooling to room temperature, H O (5 mL)
2
was added, followed by extraction with CH Cl (3 x 10 mL). The solvent was removed in
2 2
vacuo and the crude product was purified by silica gel chromatography (eluting with CH Cl )
2 2
to yield 3-formyl-4-vinylbenzoic acid methyl ester as a pale yellow solid (0.332 g, 1.75 mmol,
78%).
1H NMR (400.13 MHz, CDCl ) δ = 3.96 (s, 3H), 5.62 (dd, J = 11.2 Hz, J = 1.0 Hz, 1H), 5.82
3
(dd, J = 17.5 Hz, J = 1.0 Hz, 1H), 7.60 (dd, J = 17.5 Hz, J = 11.2 Hz, 1H), 7.66 (br d, J = 8.2
Hz, 1H), 8.20 (ddd, J = 8.2 Hz, J = 1.9 Hz, J = 0.6 Hz, 1H), 8.48 (d, J = 1.9 Hz, 1H), 10.29 (s,
1H); 13C{1H} NMR (100.6 MHz, CDCl ) δ = 52.6, 121.4, 127.8, 130.0, 132.9, 133.0, 133.3,
3
134.4, 144.3, 166.0, 191.8. HRMS (EI): Calcd. for C H O (M): 190.0630; Found:
11 10 3
190.0630.

2-bromopyridine-3-carbaldehyde6

O Freshly distilled 2-bromopyridine (16.5 g, 104 mmol) was added dropwise to a
solution of LDA at -78 °C (prepared by the dropwise addition of n-BuLi (2.5 M in
hexanes, 115 mmol, 46 mL) to a solution of i-Pr NH (135 mmol, 19.1 mL) in
2
N Br THF (250 mL) at -78 °C and stirred for 20 minutes). After 4 hours at this
temperature, freshly distilled DMF (16 mL) was added dropwise and the reaction mixture was
left to stir for further 30 minutes at -78 °C before being warmed to room temperature over 2
hours. Saturated aqueous NH Cl (100 mL) was added to the reaction mixture, followed by
4
extraction with Et O (3 x 50 mL). The combined organic extracts were washed with brine (2 x
2
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50 mL), dried over MgSO and concentrated in vacuo to yield a red oil, which was purified by
4
silica gel chromatography (eluting with n-Hexane/EtOAc, 9/1) to yield 2-bromopyridine-3-
carbaldehyde as a white crystalline solid (14.6 g, 78.3 mmol, 75%).
1H NMR (400.13 MHz, CDCl ) δ = 7.43 (ddd, J = 7.9 Hz, J = 4.7 Hz, J = 0.9 Hz, 1H), 8.17
3
(dd, J = 7.9 Hz, J = 2.2 Hz, 1H), 8.56 (dd, J = 2.2 Hz, J = 4.7 Hz, 1H), 10.33 (d, J = 0.9 Hz,
1H); 13C{1H} NMR (100.6 MHz, CDCl ) δ = 123.6, 130.7, 138.1, 145.5, 154.6, 191.2.
3
HRMS (EI): Calcd. for C H ONBr (M): 184.9476; Found: 184.9472.
6 4

2-vinylpyridine-3-carbaldehyde

O A solution of 2-bromopyridine-3-carbaldehyde (0.278 g, 1.5 mmol), potassium
vinyltrifluoroborate (0.20 g, 1.5 mmol), PdCl (5.3 mg, 0.03 mmol), PPh (23.5
2 3
mg, 0.09 mmol) and Cs CO (1.5 g, 4.5 mmol) in THF/H O (9/1) (3 mL) was
2 3 2
N heated at 85 °C for 22 hours under an argon atmosphere in a sealed tube. After
cooling to room temperature, H O (3 mL) was added, followed by extraction with CH Cl (3
2 2 2
x 10 mL). The solvent was removed in vacuo and the crude product was purified by silica gel
chromatography (eluting with CH Cl ) to yield 2-vinylpyridine-3-carbaldehyde as a pale
2 2
yellow solid (0.143 g, 1.1 mmol, 71%).
1H NMR (400.13 MHz, CDCl ) δ = 5.74 (dd, J = 10.8 Hz, J = 1.8 Hz, 1H), 6.47 (dd, J = 17.0
3
Hz, J = 1.8 Hz, 1H), 7.35 (dd, J = 7.8 Hz, J = 4.8 Hz, 1H), 7.58 (dd, J = 17.0 Hz, J = 10.8 Hz,
1H), 8.11 (dd, J = 7.8 Hz, J = 1.9 Hz, 1H), 8.75 (dd, J = 4.8 Hz, J = 1.9 Hz, 1H), 10.36 (s,
1H); 13C{1H} NMR (100.6 MHz, CDCl ) δ = 122.9, 124.1, 128.2, 131.7, 138.2, 153.6, 156.5,
3
191.0. HRMS (EI): Calcd. for C H ON (M): 133.0528; Found: 133.0528.
8 7

1-bromo-4-chloro-2-dibromomethylbenzene

Br A mixture of 2-bromo-5-chlorotoluene (12.5 g, 60.8 mmol), N-
Br bromosuccinimide (32.5 g, 182.5 mmol) and AIBN (40 mg) in anhydrous
benzene (150 mL) was stirred and held at reflux for 16 hours. (AIBN (40 mg)
Br
was added every 3 hours) After cooling to room temperature, the solvent was
Cl
removed in vacuo and the crude product was purified by silica gel
chromatography (eluting with CH Cl ) to yield 1-bromo-4-chloro-2-dibromomethylbenzene
2 2
as a pale yellow solid (15.9 g, 43.8 mmol, 72%).
1H NMR (400.13 MHz, CDCl ) δ = 6.98 (s, 1H), 7.15 (dd, J = 8.6 Hz, J = 2.5 Hz, 1H), 7.43
3
(d, J = 8.6 Hz, 1H), 8.00 (d, J = 2.5 Hz, 1H); 13C{1H} NMR (100.6 MHz, CDCl ) δ = 38.5,
3
117.7, 131.3, 131.4, 133.8, 134.7, 142.1. HRMS (EI): Calcd. for C H Br Cl (M-Br):
7 4 2
280.8368; Found: 280.8365.

2-bromo-5-chlorobenzaldehyde7

Br 1-bromo-4-chloro-2-dibromomethylbenzene (2.8 g, 7.7 mmol) in H SO (30
2 4
O mL) was heated for 3 hours at 60 °C. EtOAc (30 mL) was added and the
aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organic
layers were washed with water (30 mL) and brine (30 mL) and dried over
Cl
MgSO . After evaporation of the solvent, the crude product was purified by
4
silica gel chromatography (eluting with CH Cl ) to yield 2-bromo-5-chlorobenzaldehyde as a
2 2
white solid (1.61 g, 7.3 mmol, 95%).
1H NMR (400.13 MHz, CDCl ) δ = 7.41 (dd, J = 8.5 Hz, J = 2.7 Hz, 1H), 7.59 (d, J = 8.5
3
Hz, 1H), 7.86 (d, J = 2.7 Hz, 1H), 10.29 (s, 1H); 13C{1H} NMR (100.6 MHz, CDCl ) δ =
3
124.7, 129.8, 134.6, 134.8, 135.2, 135.3, 190.6. HRMS (EI): Calcd. for C H O BrCl (M-H):
7 3 3
216.9056; Found: 216.9051.
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Electronic Supplementary Material (ESI) for Chemical Communications
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5-chloro-2-vinylbenzaldehyde

A solution of 2-bromo-5-chlorobenzaldehyde (0.42 g, 1.9 mmol), potassium
O vinyltrifluoroborate (0.26 g, 1.9 mmol), PdCl2 (6.9 mg, 0.04 mmol), PPh3
Cl (30.5 mg, 0.12 mmol) and Cs CO (1.9 g, 5.7 mmol) in THF/H O (9/1) (3
2 3 2
mL) was heated at 85 °C for 22 hours under an argon atmosphere in a sealed tube. After
cooling to room temperature, H O (3 mL) was added, followed by extraction with CH Cl (3
2 2 2
x 10 mL). The solvent was removed in vacuo and the crude product was purified by silica gel
chromatography (eluting with CH Cl ) to yield 5-chloro-2-vinylbenzaldehyde as a pale
2 2
yellow solid (0.256 g, 1.54 mmol, 81%).
1H NMR (400.13 MHz, CDCl ) δ = 5.55 (dd, J = 11.0 Hz, J = 1.1 Hz, 1H), 5.70 (dd, J = 17.4
3
Hz, J = 1.1 Hz, 1H), 7.44 (dd, J = 17.4 Hz, J = 11.0 Hz, 1H), 7.51 (s, 1H), 7.52 (br s, 1H),
7.80 (t, J = 1.4 Hz, 1H), 10.26 (s, 1H); 13C{1H} NMR (100.6 MHz, CDCl ) δ = 120.4, 129.1,
3
130.4, 132.2, 133.9, 134.1, 134.3, 139.0, 190.9. HRMS (EI): Calcd. for C H OCl (M):
9 7
166.0185; Found: 166.0185.

5-fluoro-2-vinylbenzaldehyde8

A solution of 2-bromo-5-fluorobenzaldehyde (0.39 g, 1.9 mmol), potassium
O vinyltrifluoroborate (0.26 g, 1.9 mmol), PdCl2 (6.9 mg, 0.04 mmol), PPh3
F (30.5 mg, 0.12 mmol) and Cs CO (1.9 g, 5.7 mmol) in THF/H O (9/1) (3
2 3 2
mL) was heated at 85 °C for 22 hours under an argon atmosphere in a sealed tube. After
cooling to room temperature, H O (3 mL) was added, followed by extraction with CH Cl (3
2 2 2
x 10 mL). The solvent was removed in vacuo and the crude product was purified by silica gel
chromatography (eluting with CH Cl ) to yield 5-fluoro-2-vinylbenzaldehyde as a yellow oil
2 2
(0.231 g, 1.54 mmol, 81%).
1H NMR (300.07 MHz, CDCl ) δ = 5.53 (d, J = 11.0 Hz, 1H), 5.64 (d, J = 17.4 Hz, 1H), 7.25
3
(td, J = 8.6 Hz, J = 3.0 Hz, 1H), 7.42 (dd, J = 17.4 Hz, J = 11.0 Hz, 1H), 7.52 (dd, J = 8.6 Hz,
J = 3.0 Hz, 1H), 7.54 (dd, J = 8.6 Hz, J = 5.3 Hz, 1H), 10.31 (d, J = 2.1 Hz, 1H); 13C{1H}
NMR (100.6 MHz, CDCl ) δ = 116.2 (d, J = 22.2 Hz), 120.0 (br s), 121.3 (d, J = 22.2 Hz),
3
129.8 (d, J = 7.3 Hz), 132.1, 134.5 (d, J = 5.9 Hz), 137.1 (d, J = 3.5 Hz), 162.5 (d, J = 249.8
Hz), 190.7 (d, J = 1.8 Hz). HRMS (EI): Calcd. for C H OF (M): 150.0481; Found: 150.0478.
9 7

4-methyl-2-vinylbenzaldehyde

A solution of 2-bromo-4-methylbenzaldehyde (0.39 g, 1.9 mmol), potassium
vinyltrifluoroborate (0.26 g, 1.9 mmol), PdCl (6.9 mg, 0.04 mmol), PPh (30.5
2 3
mg, 0.12 mmol) and Cs CO (1.9 g, 5.7 mmol) in THF/H O (9/1) (3 mL) was
2 3 2
heated at 85 °C for 22 hours under an argon atmosphere in a sealed tube. After
O cooling to room temperature, H O (3 mL) was added, followed by extraction
2
with CH Cl (3 x 10 mL). The solvent was removed in vacuo and the crude product was
2 2
purified by silica gel chromatography (eluting with CH Cl ) to yield 4-methyl-2-
2 2
vinylbenzaldehyde as a pale yellow solid (0.218 g, 1.5 mmol, 77%).
1H NMR (400.13 MHz, CDCl ) δ = 2.42 (s, 3H), 5.48 (dd, J = 11.0 Hz, J = 1.3 Hz, 1H), 5.68
3
(dd, J = 17.4 Hz, J = 1.3 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.36 (s, 1H) 7.52 (dd, J = 17.4 Hz,
J = 11.0 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 10.22 (s, 1H); 13C{1H} NMR (100.6 MHz, CDCl )
3
δ = 21.9, 119.1, 128.1, 128.9, 130.8, 131.7, 133.7, 140.6, 144.8, 192.1. HRMS (EI): Calcd.
for C H O (M): 146.0732; Found: 146.0731.
10 10

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