Heterogeneous C–H Alkenylations in Continuous-Flow ... · Biotecnologie, Università di Perugia Via Elce di Sotto, 8, 06123 Perugia, Italy ‡ Institut für Organische und Biomolekulare

Heterogeneous C–H Alkenylations in Continuous-Flow:

Oxidative Palladium-Catalysis in a Biomass-Derived

Reaction Medium

Francesco Ferlin,† Stefano Santoro,† Lutz Ackermann,‡ and Luigi Vaccaro*,†

†Laboratory of Green Synthetic Organic Chemistry, Dipartimento di Chimica, Biologia e

Biotecnologie, Universita di Perugia Via Elce di Sotto, 8, 06123 Perugia, Italy ‡Institut fur Organische und Biomolekulare Chemie, Georg-August-Universitat Gottingen,

Tammannstrasse 2, 37077 Gottingen, Germany

ELECTRONIC SUPPORTING INFORMATION

Table of Contents

General information ESI 2

Typical Procedures for the Fujiwara-Moritani reaction ESI 2

Procedures for Catalyst Recovery and Recycling ESI 2

Procedures for Fujiwara-Moritani reaction in flow ESI 2

Hot-filtration test ESI 3

Hg-poisoning test ESI 3

Spectral Data ESI 4-14

Copies of NMR spectra ESI 15-38

ESI - 1

Electronic Supplementary Material (ESI) for Green Chemistry.This journal is © The Royal Society of Chemistry 2017

General Information

Unless otherwise stated, all solvents and reagents were used as obtained from commercial sources

without further purification. GC analyses were performed by using a Hewlett-Packard HP 5890A

equipped with a capillary column DB-35MS (30 m, 0.53 mm), a FID detector and hydrogen as gas carrier.

GC-EIMS analyses were carried out using a Hewlett-Packard HP 6890N Network GC system/5975 Mass

Selective Detector equipped with an electron impact ionizer at 70 eV. NMR spectra were recorded on a

Bruker DRX-ADVANCE 400 MHz (1H at 400 MHz, 13C at 100.6 MHz and 19F at 376 MHz) in DMSO-

d6 using TMS as the internal standard. Elemental Analyses were conducted on a Fisons EA1108CHN.

Melting points were measured on a Büchi 510. The amount of palladium leached in solution was

measured with an Inductive Coupled Plasma – Optical Emission Spectrometer ICP-OES 710 from

Agilent Technology. Flow procedures were performed using a Jasco PU-2080 pump and an Omnifit

Glass Column as reservoir.

Typical Procedure for the Fujiwara-Moritani Reaction in Batch

A screw capped vial equipped with a magnetic stirrer was loaded, in the given order, with p-

benzoquinone (1 mmol, 2 eq), PS-TsOH (0.5 mmol, 1 eq), acetanilide (0.5 mmol, 1 eq), Pd/C 10 wt. %

(2.5 mol % of Pd), 1 mL of GVL and the alkene (0.55 mmol, 1.1 eq). The resulting solution was stirred

at 85 °C for 24h. The reaction was left cooling to r.t and filtered through a pad of celite. A 0.5 M solution

of NaHCO3 (2 mL) was added and the aqueous layer was extracted with ethyl acetate (2 mL). The organic

layer was then washed with deionized water (3 x 20 mL), dried over anhydrous Na2SO4 and evaporated

under vacuum. The products were isolated by flash chromatography using a 4:1 mixture of petroleum

ether and ethyl acetate as eluent.

Procedure for Catalyst Recovery and Recycling

After stirring at 85 °C for 24h, the reaction mixture was filtered and the combined solids were washed

with GVL (5 mL). New substrates (1a and 2a), benzoquinone and solvent were added (without the need

of fresh PS-TsOH) and left under stirring for 24 h at 85 °C. The mixture of Pd/C and PS-TsOH could be

used for four consecutive reaction runs without appreciable loss in reactivity.

Procedure for the Fujiwara-Moritani Reaction in Flow

Preparation of the reactor

A PTFE tube (2 m, 5 mm internal diameter) was packed with 2 g of Pd/C 10 wt. % (1.88 mmol) mixed

with 55.2 g of glass beads (0.5 mm diameter). The terminations of the reactor were sealed with custom

made Derlin® septa with appropriate connections.

ESI - 2

Procedure for Fujiwara-Moritani reaction in flow at 85 °C

A pre-mixed mixture of acetanilide (1 eq), acrylate (1.1 eq), p-benzoquinone (2 eq), p-toluenesulfonic

acid monohydrate (1 eq) in GVL was charged into a glass column functioning as a reservoir. The

equipment was connected, by using the appropriate valves, to a pump and installed into a box

thermostated at 85 °C. The reaction mixture was continuously pumped (flow rate: 0.5 mL∙min-1;

residence time: 40 min) through the catalyst column and the reaction was monitored by GC. Product was

collected in fractions and palladium content of the GVL solution was periodically measured by ICP-OES

analysis. The GVL solution was poured in 0.2 M NaOH, and extracted with EtOAc. Evaporating the

organic phase under vacuum afforded a solid compound, which was washed with 0.2 M NaOH. Drying

of the solid under vacuum afforded the pure products as white crystals.

Hot-filtration test

Two reactions between substrates 1a and 2a were run in parallel, in the optimized batch conditions. After

2 hours, one of the two reactions was removed from the heating and immediately subjected to filtration

through a pad of Celite. The required amount of fresh PS-TsOH was added and the reaction was allowed

to stir at the reaction conditions for additional 22 hours. The two reactions were monitored by GC

analysis.

2h 3h 6h 24h

Control reaction 46% 68% 74% 95%

Filtered reaction 43% 45% 45% 46%

Hg-poisoning test

Two reactions between substrates 1a and 2a were run in parallel, in the optimized batch conditions. After

2 hours, in one of the two reactions 100 equivalents (relative to the catalyst) of Hg(0) were added and

the reaction was allowed to stir at the reaction conditions for additional 22 hours. The two reactions were

monitored by GC analysis.

2h 3h 6h 24h

Control reaction 46% 68% 74% 95%

Hg-poisoned reaction 47% 51% 50% 51%

ESI - 3

Chem. Name Butyl (E)-3-(2-acetamidophenyl)acrylate (3a)

Lit. Ref. J. Am. Chem. Soc., 2002, 124, 1586-1587

METHOD: A screw capped vial equipped with a magnetic stirrer was loaded with p-benzoquinone (1 mmol, 108.1 mg), PS-TsOH (0.5 mmol, 150

mg), acetanilide (0.5 mmol, 67.6 mg), Pd/C (2.5 mol %, 13.3 mg), 1 mL of GVL and butyl acrylate (0.55 mmol, 76 µL). The resulting solution was stirred at 85 °C for 24h. The reaction was left cooling to r.t and filtered through a pad of celite. A 0.5 M solution of NaHCO3 (2 mL) was added and the aqueous layer was extracted with ethyl acetate (2 mL). The organic layer was then washed with deionized water (3 x 20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. Chromatography of the crude product (PE/EtOAc 4:1) afforded the pure product as a white solid, 124 mg (95%).

Mol Formula C15H19NO3 m.p. 82-85 °C

Elemental Analysis: Calc.: C, 68.94; H, 7.33; N, 5.36. Found: C, 68.96; H, 7.32; N, 5.35.

1H NMR 400 MHz DMSO

δ value No. H Mult. J value/Hz

0.93 3 t 7.6

1.44-1.36 2 m

1.67-1.60 2 m

2.08 3 s

4.16 2 t 6.4

6.57 1 d 16.0

7.30-7.20 1 m

7.55-7.45 2 m

7.77 1 d 16.0

7.83 1 d 8.0

9.85 1 s

13C NMR (100.6 MHz, DMSO) δ : 14.1, 19.1, 23.6, 30.7, 64.2, 119.1, 126.2, 127.1, 127.3, 129.1, 131.0, 137.5, 140.7, 166.8, 169.2

GC-EIMS (m/z, %): 90 (15), 117 (45), 118 (77), 128 (20), 146 (100), 219 (16), 261 (18)

ESI - 4

Chem. Name Ethyl (E)-3-(2-acetamidophenyl)acrylate (3b)

Lit. Ref. Org. Lett., 2012, 14, 728-731

METHOD: A screw capped vial equipped with a magnetic stirrer was loaded with p-benzoquinone (1 mmol, 108.1 mg), PS-TsOH (0.5 mmol, 150 mg), acetanilide (0.5 mmol, 67.6 mg), Pd/C (2.5 mol %, 13.3 mg), 1 mL of GVL and ethyl acrylate (0.55 mmol, 60 µL). The resulting solution was stirred at 85 °C for 24h. The reaction was left cooling to r.t and filtered through a pad of celite. A 0.5 M solution of NaHCO3 (2 mL) was added and the aqueous layer was extracted with ethyl acetate (2 mL). The organic layer was then washed with deionized water (3 x 20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. Chromatography of the crude product (PE/EtOAc 4:1) afforded the pure product as a white solid, 113 mg (97%).



1H NMR 400 MHz DMSO


1.25 3 t 7.2

2.08 3 s

4.19 2 q 7.2

6.56 1 d 16.0

7.30-7.15 1 m

7.50-7.33 2 m

7.90-7.70 2 m

9.86 1 s

13C NMR (100.6 MHz, DMSO) δ : 14.6, 23.6, 60.5, 119.1, 126.2, 127.1, 127.2, 128.9, 131.0, 137.5, 140.7, 166.7, 169.2

GC-EIMS (m/z, %): 117 (45), 118 (59), 128 (22), 146 (100), 191 (25), 233 (23)

ESI - 5

Chem. Name Methyl (E)-3-(2-acetamidophenyl)acrylate (3c)

Lit. Ref. Tetrahedron Lett., 2007, 48, 5449–5453

METHOD: A screw capped vial equipped with a magnetic stirrer was loaded with p-benzoquinone (1 mmol, 108.1 mg), PS-TsOH (0.5 mmol, 150 mg), acetanilide (0.5 mmol, 67.6 mg), Pd/C (2.5 mol %, 13.3 mg), 1 mL of GVL and methyl acrylate (0.55 mmol, 50 µL). The resulting solution was stirred at 85 °C for 24h. The reaction was left cooling to r.t and filtered through a pad of celite. A 0.5 M solution of NaHCO3 (2 mL) was added and the aqueous layer was extracted with ethyl acetate (2 mL). The organic layer was then washed with deionized water (3 x 20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. Chromatography of the crude product (PE/EtOAc 4:1) afforded the pure product as a white solid, 87 mg (80%).



1H NMR 400 MHz DMSO


2.09 3 s

3.74 3 s

6.58 1 d 16.0

7.28-7.18 1 m

7.44-7.35 2 m

7.83-7.76 2 m

9.84 1 s

13C NMR (100.6 MHz, DMSO) δ : 23.6, 52.0, 118.8, 126.2, 127.0, 127.3, 128.8, 131.0, 137.5, 140.8, 167.2, 169.2

GC-EIMS (m/z, %):89 (24), 90 (26), 118 (74), 128 (31), 146 (100), 160 (24), 176 (27), 177 (30), 219 (27)

ESI - 6

Chem. Name Benzyl (E)-3-(2-acetamidophenyl)acrylate (3d)

Lit. Ref. Angew. Chem. Int. Ed., 2015, 54, 7414–7417

METHOD: A screw capped vial equipped with a magnetic stirrer was loaded with p-benzoquinone (1 mmol, 108.1 mg), PS-TsOH (0.5 mmol, 150 mg), acetanilide (0.5 mmol, 67.6 mg), Pd/C (2.5 mol %, 13.3 mg), 1 mL of GVL and benzyl acrylate (0.55 mmol, 84 µL). The resulting solution was stirred at 85 °C for 24h. The reaction was left cooling to r.t and filtered through a pad of celite. A 0.5 M solution of NaHCO3 (2 mL) was added and the aqueous layer was extracted with ethyl acetate (2 mL). The organic layer was then washed with deionized water (3 x 20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. Chromatography of the crude product (PE/EtOAc 4:1) afforded the pure product as a white solid, 99 mg (67%).



1H NMR 400 MHz DMSO


2.08 3 s

5.24 2 s

6.64 1 d 16.0

7.26-7.20 1 m

7.50-7.30 7 m

7.85-7.80 2 m

9.86 1 s

13C NMR (100.6 MHz, DMSO) δ : 23.6, 66.1, 118.8, 126.2, 127.1, 127.3, 128.51, 128.55, 128.9, 131.1, 136.7, 137.6, 141.2, 166.6,

169.2

GC-EIMS (m/z, %): 65 (16), 91 (100), 117 (29), 118 (44), 145 (15), 146 (44), 160 (15), 162 (21), 204 (20), 295 (10)

ESI - 7

Chem. Name (E)-N-(2-(2-cyanovinyl)phenyl)acetamide (3e)

Lit. Ref. Org. Lett., 2009, 11, 269–271

METHOD: A screw capped vial equipped with a magnetic stirrer was loaded with p-benzoquinone (1 mmol, 108.1 mg), PS-TsOH (0.5 mmol, 150 mg), acetanilide (0.5 mmol, 67.6 mg), Pd/C (2.5 mol %, 13.3 mg), 1 mL of GVL and acrylonitrile (0.55 mmol, 38 µL). The resulting solution was stirred at 85 °C for 24h. The reaction was left cooling to r.t and filtered through a pad of celite. A 0.5 M solution of NaHCO3 (2 mL) was added and the aqueous layer was extracted with ethyl acetate (2 mL). The organic layer was then washed with deionized water (3 x 20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. Chromatography of the crude product (PE/EtOAc 4:1) afforded the pure product as a white solid, 61 mg (66%).

Mol Formula C11H10N2O m.p. 171-174 °C


1H NMR 400 MHz DMSO


2.10 3 s

6.41 1 d 16.8

7.24 1 t 7.6

7.44 1 t 7.6

7.50 1 d 8.0

7.69 1 d 16.4

7.75 1 d 7.6

9.76 1 s

13C NMR (100.6 MHz, DMSO) δ : 23.8, 97.6, 119.5, 125.9, 126.4, 126.6, 127.8, 131.7, 137.2, 146.9 169.3

GC-EIMS (m/z, %):90 (15), 117 (62), 144 (100), 171 (18), 186 (22)

ESI - 8

Chem. Name Butyl (E)-3-(2-acetamido-5-methylphenyl)acrylate (3f)

Lit. Ref. Org. Lett., 2012, 14, 728–731

METHOD: A screw capped vial equipped with a magnetic stirrer was loaded with p-benzoquinone (1 mmol, 108.1 mg), PS-TsOH (0.5 mmol, 150 mg), 4’-methylacetanilide (0.5 mmol, 74.6 mg), Pd/C (2.5 mol %, 13.3 mg), 1 mL of GVL and butyl acrylate (0.55 mmol, 76 µL). The resulting solution was stirred at 85 °C for 24h. The reaction was left cooling to r.t and filtered through a pad of celite. A 0.5 M solution of NaHCO3 (2 mL) was added and the aqueous layer was extracted with ethyl acetate (2 mL). The organic layer was then washed with deionized water (3 x 20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. Chromatography of the crude product (PE/EtOAc 4:1) afforded the pure product as a white solid, 107 mg (78%).



1H NMR 400 MHz DMSO


0.93 3 t 7.2

1.44-1.34 2 m

1.66-1.59 2 m

2.06 3 s

2.31 3 s

4.15 2 t 6.4

6.55 1 d 16.0

7.27-7.20 2 m

7.67 1 s

7.73 1 d 16.0

9.74 1 s

13C NMR (100.6 MHz, DMSO) δ : 14.1, 19.1, 20.9, 23.6, 30.7, 64.2, 118.8, 127.1, 127.4, 128.9, 131.8, 135.1, 135.6, 140.8, 166.8,

169.2

GC-EIMS (m/z, %): 130 (26), 131 (22), 132 (65), 142 (15), 160 (100), 233 (18), 275 (25)

ESI - 9

Chem. Name Butyl (E)-3-(2-acetamido-4-chlorophenyl)acrylate (3g)

Lit. Ref. Adv. Synth. Catal., 2005, 347, 1921–1924

METHOD: A screw capped vial equipped with a magnetic stirrer was loaded with p-benzoquinone (1 mmol, 108.1 mg), PS-TsOH (0.5 mmol, 150 mg), 3’-chloroacetanilide (0.5 mmol, 84.8 mg), Pd/C (2.5 mol %, 13.3 mg), 1 mL of GVL and butyl acrylate (0.55 mmol, 76 µL). The resulting solution was stirred at 85 °C for 24h. The reaction was left cooling to r.t and filtered through a pad of celite. A 0.5 M solution of NaHCO3 (2 mL) was added and the aqueous layer was extracted with ethyl acetate (2 mL). The organic layer was then washed with deionized water (3 x 20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. Chromatography of the crude product (PE/EtOAc 4:1) afforded the pure product as a white solid, 118 mg (80%).

Mol Formula C15H18ClNO3 m.p. 152-155 °C


1H NMR 400 MHz DMSO


0.92 3 t 7.6

1.43-1.34 2 m

1.67-1.59 2 m

2.10 3 s

4.16 2 t 6.4

6.61 1 d 16.0

7.28 1 dd 8.4; 2.0

7.59 1 d 2.0

7.75 1 d 16.0

7.86 1 d 8.4

9.97 1 s

13C NMR (100.6 MHz, DMSO) δ : 14.1, 19.1, 23.7, 30.7, 64.3, 120.0, 125.9, 126.1, 127.3, 129.0, 135.0, 138.7, 139.4, 166.6, 169.4

GC-EIMS (m/z, %): 89 (17), 117 (18), 151 (40), 152 (81), 153 (22), 154 (26), 162 (17), 180 (100), 182 (33), 253 (22), 295 (17)

ESI - 10

Chem. Name Butyl (E)-3-(2-acetamido-5-bromophenyl)acrylate (3h)

Lit. Ref.

METHOD: A screw capped vial equipped with a magnetic stirrer was loaded with p-benzoquinone (1 mmol, 108.1 mg), PS-TsOH (0.5 mmol, 150 mg), 4’-bromoacetanilide (0.5 mmol, 106.5 mg), Pd/C (2.5 mol %, 13.3 mg), 1 mL of GVL and butyl acrylate (0.55 mmol, 76 µL). The resulting solution was stirred at 85 °C for 24h. The reaction was left cooling to r.t and filtered through a pad of celite. A 0.5 M solution of NaHCO3 (2 mL) was added and the aqueous layer was extracted with ethyl acetate (2 mL). The organic layer was then washed with deionized water (3 x 20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. Chromatography of the crude product (PE/EtOAc 4:1) afforded the pure product as a white solid, 129 mg (76%).

Mol Formula C15H18BrNO3 m.p. 120-123 °C


1H NMR 400 MHz DMSO


0.92 3 t 7.2

1.41-1.34 2 m

1.66-1.59 2 m

2.09 3 s

4.15 2 t 6.8

6.70 1 d 16.0

7.39 1 d 8.4

7.57 1 d 8.4

7.67 1 d 16.0

8.05 1 s

9.91 1 s

13C NMR (100.6 MHz, DMSO) δ : 14.0, 19.1, 23.6, 30.7, 64.3, 118.6, 120.7, 128.8, 129.7, 131.0, 133.5, 136.7, 139.1, 166.6, 169.2

GC-EIMS (m/z, %): 89 (20), 116 (22), 117 (44), 195 (18), 196 (28), 197 (21), 198 (28), 224 (100), 225 (22), 226 (97), 297 (25), 299

(25), 339 (19), 341 (19)

ESI - 11

Chem. Name Butyl (E)-3-(2-acetamido-4-(trifluoromethyl)phenyl)acrylate (3i)

Lit. Ref. Adv. Synth. Catal., 2011, 353, 2988–2998

METHOD: A screw capped vial equipped with a magnetic stirrer was loaded with p-benzoquinone (1 mmol, 108.1 mg), PS-TsOH (0.5 mmol, 150 mg), 3’-trifluoromethylacetanilide (0.5 mmol, 101.5 mg), Pd/C (2.5 mol %, 13.3 mg), 1 mL of GVL and butyl acrylate (0.55 mmol, 76 µL). The resulting solution was stirred at 85 °C for 24h. The reaction was left cooling to r.t and filtered through a pad of celite. A 0.5 M solution of NaHCO3 (2 mL) was added and the aqueous layer was extracted with ethyl acetate (2 mL). The organic layer was then washed with deionized water (3 x 20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. Chromatography of the crude product (PE/EtOAc 4:1) afforded the pure product as a white solid, 122 mg (74%).

Mol Formula C16H18F3NO3 m.p. 160-162 °C


1H NMR 400 MHz DMSO


0.92 3 t 7.2

1.43-1.35 2 m

1.67-1.59 2 m

2.11 3 s

4.17 2 t 6.8

6.72 1 d 16.0

7.54 1 d 8.0

7.79 1 d 16.0

7.86 1 s

8.04 1 d 8.0

10.08 1 s

13C NMR (100.6 MHz, DMSO) δ : 14.0, 19.1, 23.7, 30.7, 64.5, 122.0, 122.2, 122.9, 124.2 (JC-F = 271 Hz), 128.7, 130.5 (JC-F = 32 Hz),

132.2, 137.9, 139.1, 166.4, 169.6

19F NMR (376 MHz, DMSO) δ : -61.50

GC-EIMS (m/z, %):57 (19), 166 (31), 185 (68), 186 (100), 187 (18), 196 (35), 213 (29), 214 (100), 215 (31), 228 (28), 287 (30), 329

(23)

ESI - 12

Chem. Name Butyl (E)-3-(2-acetamido-5-fluorophenyl)acrylate (3j)

Lit. Ref. Org. Lett., 2012, 14, 728–731

METHOD: A screw capped vial equipped with a magnetic stirrer was loaded with p-benzoquinone (1 mmol, 108.1 mg), PS-TsOH (0.5 mmol, 150 mg), 4’-fluoroacetanilide (0.5 mmol, 76.5 mg), Pd/C (2.5 mol %, 13.3 mg), 1 mL of GVL and butyl acrylate (0.55 mmol, 76 µL). The resulting solution was stirred at 85 °C for 24h. The reaction was left cooling to r.t and filtered through a pad of celite. A 0.5 M solution of NaHCO3 (2 mL) was added and the aqueous layer was extracted with ethyl acetate (2 mL). The organic layer was then washed with deionized water (3 x 20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. Chromatography of the crude product (PE/EtOAc 4:1) afforded the pure product as a white solid, 114 mg (82%).

Mol Formula C15H18FNO3 m.p. 137-140 °C


1H NMR 400 MHz DMSO


0.93 3 t 7.2

1.44-1.34 2 m

1.67-1.60 2 m

2.07 3 s

4.16 2 t 6.4

6.68 1 d 16.0

7.29-7.24 1 m

7.42-7.38 1 m

7.68 1 d 16.0

7.76-7.72 1 m

9.83 1 s

13C NMR (100.6 MHz, DMSO) δ : 14.0, 19.1, 23.5, 30.7, 64.3, 113.3 (JC-F = 23 Hz), 117.9 (JC-F = 23 Hz), 120.6, 129.4 (JC-F = 8 Hz),

131.3 (JC-F = 8 Hz), 133.8, 139.5, 160.2 (JC-F = 241 Hz), 166.6, 169.3

19F NMR (376 MHz, DMSO) δ : -116.2 (m)

GC-EIMS (m/z, %): 135 (29), 136 (44), 164 (100), 237 (22), 279 (15)

ESI - 13

Chem. Name Butyl (E)-3-(2-acetamido-5-methoxyphenyl)acrylate (3k)

Lit. Ref. J. Am. Chem. Soc., 2002, 124, 1586-1587

METHOD: A screw capped vial equipped with a magnetic stirrer was loaded with p-benzoquinone (1 mmol, 108.1 mg), PS-TsOH (0.5 mmol, 150 mg), 4’-methoxyacetanilide (0.5 mmol, 82.6 mg), Pd/C (5 mol %, 26.6 mg), 1 mL of GVL and butyl acrylate (1 mmol, 143 µL). The resulting solution was stirred at 85 °C for 48h. The reaction was left cooling to r.t and filtered through a pad of celite. A 0.5 M solution of NaHCO3 (2 mL) was added and the aqueous layer was extracted with ethyl acetate (2 mL). The organic layer was then washed with deionized water (3 x 20 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. Chromatography of the crude product (PE/EtOAc 95:5) afforded the pure product as a white solid, 106 mg (73%).



1H NMR 400 MHz DMSO


0.93 3 t 7.6

1.45-1.30 2 m

1.67-1.59 2 m

2.05 3 s

3.80 3 s

4.16 2 t 6.8

6.66 1 d 16.0

6.99 1 dd 8.8; 2.8

7.23 1 d 8.8

7.34 1 d 2.8

7.70 1 d 15.6

9.67 1 s

13C NMR (100.6 MHz, DMSO) δ : 14.1, 19.1, 23.4, 30.7, 56.0, 64.2, 110.7, 117.8, 119.5, 129.0, 130.6, 130.7, 140.6, 157.6, 166.8,

169.3

GC-EIMS (m/z, %): 132 (17), 148 (36), 176 (100), 249 (20), 291 (37)

ESI - 14

11 10 9 8 7 6 5 4 3 2 1 0 ppm

0.909

0.927

0.946

1.346

1.364

1.382

1.401

1.420

1.438

1.598

1.614

1.634

1.651

1.668

2.084

4.143

4.159

4.176

6.553

6.592

7.217

7.228

7.238

7.247

7.258

7.401

7.410

7.758

7.798

7.824

7.844

9.847

3.177

2.225

2.224

3.062

2.140

1.066

1.052

2.162

1.097

1.091

1.000

Butyl (E)-3-(2-acetamidophenyl)acrylate (3a)

ESI - 15

180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm

14.059

19.146

23.586

30.748

64.199

119.081

126.238

127.105

127.276

129.057

130.998

137.549

140.739

166.800

169.184

Butyl (E)-3-(2-acetamidophenyl)acrylate (3a)

ESI - 16

11 10 9 8 7 6 5 4 3 2 1 0 ppm

1.236

1.254

1.272

2.079

4.163

4.180

4.198

4.215

6.547

6.587

7.224

7.233

7.243

7.255

7.395

7.405

7.752

7.792

7.810

7.830

9.858

3.192

3.166

2.237

1.083

1.081

2.162

2.085

1.000

Ethyl (E)-3-(2-acetamidophenyl)acrylate (3b)

ESI - 17

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

14.646

23.595

60.514

119.094

126.188

127.053

127.249

128.930

130.973

137.497

140.661

166.744

169.217

Ethyl (E)-3-(2-acetamidophenyl)acrylate (3b)

ESI - 18

11 10 9 8 7 6 5 4 3 2 1 ppm

2.090

3.738

6.561

6.601

7.225

7.239

7.251

7.259

7.414

7.420

7.769

7.809

7.832

9.845

3.025

3.013

1.013

1.012

2.071

2.028

1.000

Methyl (E)-3-(2-acetamidophenyl)acrylate (3c)

ESI - 19

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm

23.632

51.973

118.825

126.158

127.021

127.277

128.848

131.018

137.519

140.771

167.177

169.201

Methyl (E)-3-(2-acetamidophenyl)acrylate (3c)

ESI - 20

11 10 9 8 7 6 5 4 3 2 1 ppm

2.080

5.241

6.625

6.664

7.218

7.228

7.238

7.247

7.258

7.354

7.371

7.388

7.406

7.416

7.426

7.447

7.810

7.835

7.850

9.859

3.066

2.155

1.078

1.113

7.486

2.151

1.000

Benzyl (E)-3-(2-acetamidophenyl)acrylate (3d)

ESI - 21

180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm

23.610

66.070

118.770

126.227

127.068

127.333

128.508

128.546

128.941

131.120

136.723

137.613

141.246

166.607

169.204

Benzyl (E)-3-(2-acetamidophenyl)acrylate (3d)

ESI - 22

11 10 9 8 7 6 5 4 3 2 1 ppm

2.102

6.393

6.435

7.220

7.238

7.257

7.419

7.438

7.457

7.494

7.514

7.673

7.714

7.747

7.766

9.757

3.170

1.123

1.121

1.185

1.092

1.169

1.122

1.000

(E)-N-(2-(2-cyanovinyl)phenyl)acetamide (3e)

ESI - 23

180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm

23.841

97.647

119.505

125.854

126.379

126.572

127.850

131.671

137.165

146.869

169.343

(E)-N-(2-(2-cyanovinyl)phenyl)acetamide (3e)

ESI - 24

11 10 9 8 7 6 5 4 3 2 1 ppm

0.908

0.926

0.945

1.345

1.363

1.381

1.400

1.419

1.438

1.593

1.610

1.629

1.646

1.663

2.059

2.307

4.136

4.152

4.168

6.534

6.574

7.203

7.223

7.251

7.261

7.272

7.666

7.717

7.757

9.742

3.229

2.215

2.231

3.012

3.136

2.175

1.005

2.151

1.071

1.125

1.000

Butyl (E)-3-(2-acetamido-5-methylphenyl)acrylate (3f)

ESI - 25

180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm

14.058

19.145

20.882

23.522

30.742

64.156

118.800

127.144

127.412

128.928

131.761

135.109

135.565

140.818

166.825

169.168

Butyl (E)-3-(2-acetamido-5-methylphenyl)acrylate (3f)

ESI - 26

11 10 9 8 7 6 5 4 3 2 1 0 ppm

0.906

0.924

0.943

1.342

1.360

1.378

1.397

1.416

1.434

1.595

1.612

1.632

1.649

1.666

2.100

4.144

4.161

4.177

6.589

6.629

7.269

7.274

7.291

7.295

7.585

7.590

7.730

7.770

7.855

7.876

9.975

3.299

2.263

2.202

3.173

2.189

1.075

1.066

1.004

1.087

1.084

1.000

Butyl (E)-3-(2-acetamido-4-chlorophenyl)acrylate (3g)

ESI - 27

190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm

14.055

19.128

23.719

30.731

64.290

119.965

125.901

126.074

127.307

129.045

134.959

138.664

139.383

166.652

169.435

Butyl (E)-3-(2-acetamido-4-chlorophenyl)acrylate (3g)

ESI - 28

11 10 9 8 7 6 5 4 3 2 1 0 ppm

0.901

0.920

0.938

1.340

1.357

1.375

1.394

1.413

1.431

1.588

1.604

1.623

1.641

1.658

2.086

4.137

4.153

4.169

6.680

6.720

7.381

7.402

7.562

7.583

7.657

7.697

8.048

9.912

3.405

2.164

2.106

3.369

2.072

1.078

1.123

1.057

1.080

1.039

1.000

Butyl (E)-3-(2-acetamido-5-bromophenyl)acrylate (3h)

ESI - 29

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm

14.045

19.103

23.605

30.681

64.288

118.616

120.719

128.790

129.734

130.966

133.495

136.696

139.100

166.600

169.243

Butyl (E)-3-(2-acetamido-5-bromophenyl)acrylate (3h)

ESI - 30

11 10 9 8 7 6 5 4 3 2 1 ppm

0.900

0.919

0.937

1.357

1.375

1.394

1.413

1.431

1.596

1.613

1.632

1.649

1.666

2.114

4.154

4.170

4.187

6.700

6.740

7.531

7.551

7.778

7.818

7.864

8.036

8.056

10.084

3.591

2.440

2.320

3.148

2.188

1.201

1.078

1.072

1.075

1.076

1.000

Butyl (E)-3-(2-acetamido-4-(trifluoromethyl)phenyl)acrylate (3i)

ESI - 31

2030405060708090100110120130140150160170180 ppm

14.053

19.123

23.734

30.704

64.455

122.012

122.170

122.862

122.971

125.569

128.276

128.708

130.072

130.391

130.710

131.027

132.196

137.924

139.105

166.436

169.605


ESI - 32

-35 -40 -45 -50 -55 -60 -65 -70 -75 -80 ppm

-61.501


ESI - 33

11 10 9 8 7 6 5 4 3 2 1 ppm

0.907

0.926

0.944

1.344

1.362

1.380

1.399

1.418

1.436

1.596

1.612

1.632

1.649

1.666

2.072

4.145

4.162

4.178

6.666

6.706

7.236

7.243

7.258

7.265

7.279

7.286

7.380

7.394

7.402

7.416

7.665

7.668

7.705

7.708

7.725

7.732

7.750

7.757

9.832

3.139

2.174

2.143

3.021

2.068

1.028

1.101

1.064

1.053

1.038

1.000

Butyl (E)-3-(2-acetamido-5-fluorophenyl)acrylate (3j)

ESI - 34

180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm

14.050

19.130

23.455

30.710

64.322

113.215

113.447

117.803

118.030

120.645

129.346

129.431

131.243

131.327

133.852

139.513

158.997

161.405

166.624

169.341


ESI - 35

-102 -104 -106 -108 -110 -112 -114 -116 -118 -120 -122 -124 -126 -128 ppm

-116.230

-116.214

-116.209

-116.193

-116.187

-116.171

-116.167


ESI - 36

11 10 9 8 7 6 5 4 3 2 1 0 ppm

0.909

0.927

0.946

1.366

1.384

1.403

1.422

1.597

1.613

1.633

1.650

1.667

2.046

3.804

4.141

4.157

4.174

6.642

6.682

6.975

6.982

6.997

7.004

7.223

7.245

7.346

7.353

7.682

7.721

9.667

3.193

2.145

2.225

3.093

3.187

2.110

1.033

1.049

1.061

1.030

1.058

1.000

Butyl (E)-3-(2-acetamido-5-methoxyphenyl)acrylate (3k)

ESI - 37

180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ppm

14.054

19.147

23.385

30.740

55.951

64.195

110.693

117.841

119.469

128.987

130.650

130.743

140.626

157.596

166.845

169.280

Butyl (E)-3-(2-acetamido-5-methoxyphenyl)acrylate (3k)

ESI - 38

Documents

Heterogeneous C–H Alkenylations in Continuous-Flow ... · Biotecnologie, Università di Perugia Via Elce di Sotto, 8, 06123 Perugia, Italy ‡ Institut für Organische und Biomolekulare