Synthesis of monosubstituted 1,1-dicarbonyl ester 1,3-dienes

Article abstract of DOI:10.1055/s-0033-1340468

The synthesis of various electron-deficient 1,1-dicarbonyl ester 1,3-dienes substituted in position 2 or 3 of the diene moiety has been developed. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1340468

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Synthetic Organic Chemistry
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SUPPORTING INFORMATION
Supporting Information
for DOI: 10.1055/s-0033-1340468
© Georg Thieme Verlag KG Stuttgart · New York 2013
Thieme

Synthesis of Monosubstituted 1,1-Dicarbonyl Ester 1,3-Dienes
Olivier Rousseau, Thierry Delaunay, Raphaël Robiette*
Institute of Condensed Matter and Nanosciences, Université catholique de Louvain, Place Louis Pasteur 1, L4.01.02, 1348
Louvain-la-Neuve, Belgium.
Fax +32(0)10474168; E-mail: raphael.robiette@uclouvain.be.
Supporting Information
Table of Contents
1. General
2. Experimental details and products characterization
1

1. General
Solvents: unless mentioned, all solvents (for reactions, extractions or purification by chromatography) were used
without further purification.
Reactants and reagents: commercially available reagents were used as purchased.
Thin layer chromatographies (TLCs): TLCs were carried out on Merck Silica gel 60 F254 aluminium backed plates
using UV light, potassium permanganate or p-anisaldehyde solution as revelator.
Flash chromatographies: flash chromatographies were performed using Merck Silica gel 60Å (40-63 μm).
Nuclear magnetic resonance (NMR) spectroscopy: NMR spectra were recorded either on a 300 MHz Bruker avance
II 300 or on a 500 MHz Bruker avance 500 spectrometer in the indicated solvent. Chemical shifts are given in ppm
relative to the reference (TMS) and coupling constants are given in Hz. For some molecules, the 1H and 13C signals’
attributions required additional analysis (COSY, HMQC, HMBC, 13C DEPT-135).
Mass spectrometry: mass spectra and high resolution mass spectra were obtained on a Thermo Orbitrap Exactive
device. The mass are given in Dalton.
Infra-red spectroscopy: Infra-red spectra were obtained on a Shimadzu FTIR-8400S device. Absorption frequencies
are given in cm-1.
2

2. Experimental details and products characterization
2.1. Synthesis of 3-substituted dicarbonyl ester 1,3-dienes
2.1.1. Dimethyl (2-methylprop-2-en-1-ylidene)malonate (2a)
Procedure:
In a dry round bottom flask was added 12 mL of THF under inert atmosphere. A solution of TiCl4 (6 mmol)
in 1.5 mL of CCl4 was then added, slowly, at 0 °C. After 10 min stirring at 0 °C, methacrolein (3 mmol) and
dimethyl malonate (1.5 mmol) were added, slowly. After 20 min stirring at 0 °C, pyridine (12 mmol) was added,
slowly, at 0 °C. After 16 h of stirring at room temperature, the reaction mixture was diluted with Et2O (10 mL) and
water (10 mL). The layers were separated and the aqueous layer was extracted twice with Et2O (2*10 mL). The
combined organic layers were washed with a NaHCO3sat solution (10 mL) and then brine (10 mL). The organic layer
was dried over Na2SO4, filtered and concentrated under reduced pressure.
CAS Reg. No. 63646-70-8
Yield : 77%
Mol. formula: C9H12O4
Mol. Wt. : 184.19 g.mol-1
Aspect: colorless liquid
1H NMR (300 MHz, CDCl3): δ 7.34 (s, 1H, HC=C), 5.38 (s, 1H, H2C=C), 5.33 (s, 1H, H2C=C), 3.76 (s, 3H, O-
CH3), 3.72 (s, 3H, O-CH3), 1.80 (s, 3H, C=CH3).
13C NMR (125 MHz, CDCl3): δ 167.0, 164.8, 144.5, 139.3, 127.9, 124.6, 52.6, 52.5, 18.8.
1H and 13C NMR spectra were in accord with literature; see Matsuki, T.; Hu, N. X.; Aso, Y.; Otsubo, T.; Ogura, F.
Bull. Chem. Soc. Jpn. 1989, 62, 2105.
3

2.1.2. Dimethyl (2-phenylprop-2-en-1-ylidene)malonate (2b)
Procedure:
In a dry round bottom flask was added 6 mL of THF under inert atmosphere. A solution of TiCl4 (3 mmol)
in 1 mL of CCl4 was then added, slowly, at 0 °C. After 10 min stirring at 0 °C, atropaldehyde1 (1.5 mmol) diluted in
0.2 mL THF and dimethyl malonate (0.8 mmol) were added, slowly, at -78 °C. After 40 min stirring at -78 °C,
pyridine (7 mmol) was added, slowly, at -78 °C. The cooling bath was then removed. When the reaction mixture
reached room temperature, it was refluxed for 2h. Then, after cooling, the reaction mixture was diluted with Et2O (10
mL) and water (10 mL). The layers were separated and the aqueous layer was extracted twice with Et2O (2*10 mL).
The organic layers were combined, washed with a NaHCO3sat solution (10 mL) and brine (10 mL). The organic layer
was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash
chromatography (05/95 EtOAc/cyclohexane).
Yield : 34%
Mol. formula: C14H14O4
Mol. Wt. : 246.26 g.mol-1
Aspect: colorless liquid
1H NMR (300 MHz, CDCl3): δ 7.63 (s, 1H, HC=C), 7.38 – 7.27 (massif, 5H, Ar), 5.65 (s, 2H, H2C=C), 3.82 (s, 3H,
O-CH3), 3.34 (s, 3H, O-CH3).
13C NMR (125 MHz, CDCl3): δ 165.8, 164.6, 144.2, 138.2, 128.5, 128.4, 127.8, 127.5, 123.8, 52.8, 52.2 (one
quaternary carbon is not observed).
FT-IR (cm-1): 3028, 2951, 1728, 1620, 1603, 1495, 1435, 1364, 1315, 1300, 1244, 1184, 1067, 1005, 916, 843, 777,
752, 704.
MS (APCI): m/z = 247 [M + H]+, 216 [M – CH3O]+.
HRMS (APCI): m/z = 247.09680 [M + H]+; calcd. for C14H15O4: 247.09649.
1 C. Nsanzumuhire, J.-L. Clément, O. Ouari, H. Karoui, J.-P. Finet, P. Tordo, Tetrahedron Letters 2004, 45,
6385.
4

2.2. Synthesis of 2-Substituted dicarbonyl ester 1,3-Dienes
2.2.1. Knoevenagel Condensation
General procedure:
In a round bottom flask was added malonate (93 mmol) and aldehyde (110 mmol) in absolute ethanol (40
mL), then acetic acid (17 mmol) and piperidine (15 mmol). The reaction vessel was heated to reflux for 48 hours2.
Then by-product was distilled in a Kugelrohr apparatus under vacuum. The desired compound was obtained with an
excellent yield.
diethyl benzylidenemalonate (4a)
CAS Reg. No. 5292-53-5
Yield : 88%
Mol. formula: C14H16O4
Mol. Wt. : 248.27 g.mol-1
Aspect: yellow oil
1H NMR (300 MHz, CDCl3): δ 7.74 (s, 1H, HCAr), 7.47 – 7.37 (massif, 5H, Ar), 4.32 (m, 4H, 2*H2C-CH3), 1.34 (t,
J = 7.2 Hz, 3H, H2C-CH3), 1.29 (t, J = 7.2 Hz, 3H, H2C-CH3).
13C NMR (75 MHz, CDCl3): δ 166.2, 163.7, 141.6, 132.6, 130.2, 129.1, 128.5, 126.1, 61.3, 61.2, 13.8, 13.5.
1H and 13C NMR spectra were in accord with literature; see Meskini, I.; Toupet, L.; Daoudi, M.; Kerbal, A.; Akkurt,
M.; Chohan, Z. H.; Ben Hadda, T. J. Chem. Crystallogr. 2010, 40, 812.
2 For R = n-Bu (4h), the mixture was stirred 16h at room temperature and then concentrated under vacuum.
The residue was diluted with AcOEt (50 mL), H2O (20 mL) and HCl 1N (10 mL). The aqueous layer was extracted
two more times with AcOEt (20 mL). The combined organic layers were washed with brine (20 mL), dried over
MgSO4 and then concentrated under vacuum. The residue was purified by flash chromatography (4/96 => 10/90
AcOEt/cyclohexane) to give the desired compound in 43% yield.
5

diethyl (4-chlorobenzylidene)malonate (4b)
CAS Reg. No. 6827-40-3
Yield : 92%
Mol. formula: C14H15ClO4
Mol. Wt. : 282.72 g.mol-1
Aspect: yellow oil
1H NMR (300 MHz, CDCl3): δ 7.67 (s, 1H, HCAr), 7.41 – 7.32 (massif, 4H, Ar), 4.32 (m, 4H, 2*H2C-CH3), 1.33 (t,
J = 7.2 Hz, 3H, H2C-CH3), 1.29 (t, J = 7.2 Hz, 3H, H2C-CH3).
13C NMR (75 MHz, CDCl3): δ 166.6, 164.0, 140.8, 136.7, 131.5, 130.8, 129.2, 127.0, 62.0, 61.9, 14.3, 14.0.
1H and 13C NMR spectra were in accord with literature; see Meskini, I.; Toupet, L.; Daoudi, M.; Kerbal, A.; Ben
Hadda, T. J. Chem. Crystallogr. 2011, 41, 891.
diethyl (4-fluorobenzylidene)malonate (4c)
CAS Reg. No. 790-53-4
Yield : 99%
Mol. formula: C14H15FO4
Mol. Wt. : 266.26 g.mol-1
Aspect: yellow oil
1H NMR (300 MHz, CDCl3): δ 7.69 (s, 1H, HCAr), 7.46 (m, 2H, Ar), 7.07 (dd, 2H, J = 8.7, 8.7 Hz, Ar), 4.34 (q,
2H, J = 7.2 Hz, CH2CH3), 4.31 (q, 2H, J = 7.2 Hz, CH2CH3), 1.33 (t, 3H, J = 7.2 Hz, CH2CH3), 1.30 (t, 3H, J = 7.2
Hz, CH2CH3).
13C NMR (75 MHz, CDCl3): δ 166.7, 164.0 (d, J = 251.2 Hz), 164.1, 140.9, 131.7 (d, J = 8.6 Hz), 129.2 (d, J = 3.2
Hz), 126.2, 116.1 (d, J = 21.7 Hz), 61.9, 61.8, 14.2, 14.0.
FT-IR (cm-1): 1724, 1634, 160, 1510, 1259, 1238, 1223, 1213, 1196, 1163, 1065, 835.
MS (APCI): m/z = 267 [M + H]+, 221 [M – C2H5O]+.
HRMS (APCI): m/z = 267.10268 [M + H]+; calcd. for C14H16O4F: 267.10271.
6

diethyl (4-fluorobenzylidene)malonate (4d)
CAS Reg. No. 14111-33-2
Yield : >99%
Mol. formula: C14H18O4
Mol. Wt. : 262.30 g.mol-1
Aspect: yellow oil
1H NMR (300 MHz, CDCl3): δ 7.70 (s, 1H, HCAr), 7.35 (d, 2H, J = 8.1 Hz, Ar), 7.18 (d, 2H, J = 8.1 Hz, Ar), 4.34
(q, 2H, J = 7.2 Hz, CH2CH3), 4.30 (q, 2H, J = 7.2 Hz, CH2CH3), 2.36 (s, 3H, H3CAr), 1.33 (t, 3H, J = 7.2 Hz,
CH2CH3), 1.30 (t, 3H, J = 7.2 Hz, CH2CH3).
13C NMR (75 MHz, CDCl3): δ 167.1, 164.4, 142.3, 141.3, 130.2, 129.7, 129.7, 125.3, 61.8, 61.7, 21.6, 14.3, 14.0.
1H and 13C NMR spectra were in accord with literature; see Kim, J. K.; Kwon, P. S.; Kwon, T. W.; Chung, S. K.;
Lee, J. W. Synth. Commun,, 1996, 26, 535.
diethyl (4-methoxybenzylidene)malonate (4e)
CAS Reg. No. 6768-23-6
Yield : 90%
Mol. formula: C15H18O5
Mol. Wt. : 278.30 g.mol-1
Aspect: yellow oil
1H NMR (300 MHz, CDCl3): δ 7.67 (s, 1H, HC-Ar), 7.42 (m, 2H, Ar), 6.88 (m, 2H, Ar), 4.35 (q, J = 7.1 Hz, 2H,
CH2-CH3), 4.29 (q, J = 7.1 Hz, 2H, CH2-CH3), 3.83 (s, 3H, H3C-O-Ar), 1.320 (t, J = 7.1 Hz, 3H, CH2-CH3), 1.316 (t,
J = 7.1 Hz, 3H, CH2-CH3).
MS (APCI): m/z = 279 [M + H]+, 233 [M – C2H5O]+.
HRMS (APCI): m/z = 279.12278 [M + H]+; calcd. for C15H19O5: 279.12270.
1H and mass spectra were in accord with literature; see Delgado, F.; Tamariz, J.; Zepeda, G.; Landa, M.; Miranda,
R.; García, J. Synth. Commun. 1995, 25, 753.
7

diethyl (2-methylpropylidene)malonate (4f)
CAS Reg. No. 5652-68-6
Yield : 92%
Mol. formula: C11H18O4
Mol. Wt. : 214.26 g.mol-1
Aspect: yellow oil
1H NMR (300 MHz, CDCl3): δ 6.77 (d, J = 10.6 Hz, 1H, HC-(CO2Et)2), 4.29 (q, J = 7.1 Hz, 2H, CH2-CH3), 4.22 (q,
J = 7.1 Hz, 2H, CH2-CH3), 2.68 (m, 1H, HC(CH3)2), 1.32 (t, J = 7.1 Hz, 3H, CH2-CH3), 1.28 (t, J = 7.1 Hz, 3H, CH2-
CH3), 1.06 (d, J = 6.6 Hz, 6H, HC(CH3)2).
MS (APCI): m/z = 215 [M + H]+, 169 [M – C2H5O]+.
HRMS (APCI): m/z = 215.12783 [M + H]+; calcd. for C11H19O4: 215.12779.
1H and mass spectra were in accord with literature; see Schuppan, J.; Minnaard, A. J.; Feringa, B. L. Chem Commun
2004, 40, 792.
diethyl pentylidenemalonate (4h)
CAS Reg. No. 18795-86-3
Yield : 43%
Mol. formula: C12H20O4
Mol. Wt. : 228.28 g.mol-1
Aspect: very pale yellow turbid liquid
1H NMR (300 MHz, CDCl3): δ 6.99 (t, J = 7.9 Hz, 1H, HC-(CO2Et)2), 4.30 (q, J = 7.1 Hz, 2H, O-CH2-CH3), 4.23
(q, J = 7.1 Hz, 2H, O-CH2-CH3), 2.29 (dt, J = 7.5, 7.5 Hz, 2H, HC-CH2), 1.52 – 1.24 (massif, 4H, CH3-(CH2)2), 1.32
(t, J = 7.1 Hz, 3H, O-CH2-CH3), 1.29 (t, J = 7.1 Hz, 3H, O-CH2-CH3), 0.90 (t, J = 7.2 Hz, 3H, H3C-(CH2)3).
MS (APCI): m/z = 229 [M + H]+, 183 [M – C2H5O]+.
HRMS (APCI): m/z = 229.14424 [M + H]+; calcd. for C12H21O4: 229.14344.
The analyses’ results were in accord with literature; see Cahiez, G.; Alami, M. Tetrahedron 1989, 45, 4163.
8

2.2.2. Wittig olefination3
Procedure3:
In a round bottom flask was added diethyl malonate (4 mmol), (carbethoxymethylene)triphenyl-
phosphorane (4 mmol) and 5 mL of toluene at 0 °C under inert atmosphere. The reaction mixture was stirred 3 h at
room temperature. After concentration under reduced pressure, the residue was purified by flash chromatography
(20/80 EtOAc/cyclohexane).
Diethyl Ethoxycarbonylbutendienoate (4g)
CAS Reg. No. 13049-86-0
Yield : 98%
Mol. formula: C11H16O6
Mol. Wt. : 244.24 g.mol-1
Aspect: colorless liquid
1H NMR (500 MHz, CDCl3): δ 6.87 (s, 1H, HC-CO2Et), 4.38 (q, J = 7.2 Hz, 2H, CH2-CH3), 4.30 (q, J = 7.2 Hz, 2H,
CH2-CH3), 4.25 (q, J = 7.2 Hz, 2H, CH2-CH3), 1.36 (t, J = 7.0 Hz, 3H, CH2-CH3), 1.34 – 1.29 (m, 6H, 2*CH2-CH3).
13C NMR (75 MHz, CDCl3): δ 164.4, 163.7, 162.4, 139.0, 130.2, 62.6, 62.2, 61.9, 14.12, 14.10, 14.06.
1H and 13C NMR spectra were in accord with literature; see Okuro, K. ; Alper, H. J Org Chem 2012, 77, 4420.
2.2.3. Bromination
General procedure:
In a round bottom flask was added compound 4 (7 mmol) and bromine (8 mmol) in CCl4 (4 mL) at 0 °C.
The reaction mixture was stirred at this temperature for 1 h and then warmed to room temperature for 3 h. The
solution was diluted with dichloromethane (30 mL) then washed with a 10% NaOH solution (15 mL) and brine (10
3 Okuro, K. ; Alper, H. J Org Chem 2012, 77, 4420.
9

mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The desired
compound was used in the next step without further purification.
diethyl bromo[bromo(phenyl)methyl]malonate (5a)
CAS Reg. No. 77752-84-2
Yield : 97%
Mol. formula: C14H16Br2O4
Mol. Wt. : 408.08 g.mol-1
Aspect: yellow oil
1H NMR (300 MHz, CDCl3): δ 7.58 (m, 2H, Ar), 7.34 – 7.25 (massif, 3H, Ar), 5.77 (s, 1H, HCAr), 4.36 (m, 2H,
H2C-CH3), 4.16 (q, J = 7.2 Hz, 2H, H2C-CH3), 1.34 (t, J = 7.2 Hz, 3H, H2C-CH3), 1.19 (t, J = 7.2 Hz, 3H, H2C-CH3).
13C NMR (75 MHz, CDCl3): δ 164.5, 164.5, 136.4, 130.0, 129.4, 128.1, 68.7, 63.9, 63.8, 53.3, 14.0, 13.8.
FT-IR (cm-1): 2992, 1743, 1465, 1451, 1367, 1237, 1190, 1095, 1016, 992, 861, 756, 698, 671.
MS (APCI): m/z = 409 [M(79Br81Br) + H]+, 249 [M – Br2 + H]+, 203 [M – Br2 – C2H5O]+.
HRMS (APCI): m/z = 406.94901 [M + H]+; calcd. for C14H17O479Br2: 406.94881.
diethyl bromo[bromo(4-chlorophenyl)methyl]malonate (5b)
CAS Reg. No. 77752-87-5
Yield : 97%
Mol. formula: C14H15Br2ClO4
Mol. Wt. : 442.53 g.mol-1
Aspect: yellow oil
1H NMR (300 MHz, CDCl3): δ 7.54 (d, J = 8.7 Hz, 2H, Ar), 7.29 (d, J = 8.7 Hz, 2H, Ar), 5.73 (s, 1H, HCAr), 4.36
(m, 2H, H2C-CH3), 4.18 (q, J = 7.2 Hz, 2H, H2C-CH3), 1.34 (t, J = 7.2 Hz, 3H, H2C-CH3), 1.21 (t, J = 7.2 Hz, 3H,
H2C-CH3).
13C NMR (75 MHz, CDCl3): δ 164.3, 164.2, 135.2, 134.9, 131.4, 128.1, 68.3, 63.9, 63.8, 52.3, 13.9, 13.8.
FT-IR (cm-1): 2983, 1741, 1592, 1482, 1457, 1399, 1377, 1242, 1197, 1096, 1019, 862, 826, 730, 678.
10

MS (APCI): m/z = 443 [M(35Cl,79Br,81Br) + H]+, 283 [M(35Cl) – Br2+ H]+, 237 [M(35Cl) – Br2 – C2H5O]+.
HRMS (APCI): m/z = 440.90980 [M + H]+; calcd. for C14H16O479Br235Cl: 440.90984.
diethyl bromo[bromo(4-fluorophenyl)methyl]malonate (5c)
Yield : 87%
Mol. formula: C14H15Br2FO4
Mol. Wt. : 426.07 g.mol-1
Aspect: orange oil
1H NMR (300 MHz, CDCl3): δ 7.58 (m, 2H, Ar), 7.00 (dd, J = 8.6, 8.6 Hz, 2H, Ar), 5.75 (s, 1H, HCAr), 4.36 (m,
2H, CH2CH3), 4.17 (q, J = 7.1 Hz, 2H, CH2CH3), 1.3 (t, J = 7.1 Hz, 3H, CH2CH3), 1.2 (t, J = 7.1 Hz, 3H, CH2CH3).
13C NMR (75 MHz, CDCl3): δ 164.4, 164.3, 163.0 (d, J = 248.2 Hz), 132.3 (d, J = 3.2 Hz), 132.0 (d, J = 8.3 Hz),
114.9 (d, J = 21.7 Hz), 68.6, 63.9, 63.7, 52.3, 13.9, 13.7.
FT-IR (cm-1): 1743, 1605, 1508, 1466, 1445, 1367, 1300, 1238, 1227, 1207, 1194, 1163, 1099, 1026, 1016, 839.
MS (APCI): m/z = 427 [M(79Br81Br) + H]+, 267 [M – Br2 + H]+, 221 [M – Br2 – C2H5O]+.
HRMS (APCI): m/z = 424.93937 [M + H]+; calcd. for C14H16O479Br2F: 424.93939.
diethyl bromo[bromo(4-methylphenyl)methyl]malonate (5d)
Yield : 95%
Mol. formula: C15H18Br2O4
Mol. Wt. : 422.11 g.mol-1
Aspect: orange oil
1H NMR (300 MHz, CDCl3): δ 7.46 (d, J = 8.2 Hz, 2H, Ar), 7.11 (d, J = 8.0 Hz, 2H, Ar), 5.75 (s, 1H, HCAr), 4.35
(m, 2H, CH2CH3), 4.17 (q, J = 7.1 Hz, 2H, CH2CH3), 2.33 (s, 3H, H3CAr), 1.34 (t, J = 7.1 Hz, 3H, CH2CH3), 1.20 (t,
J = 7.1 Hz, 3H, CH2CH3).
13C NMR (75 MHz, CDCl3): δ 164.6, 164.6, 139.5, 133.5, 129.8, 128.8, 68.9, 63.8, 63.7, 53.3, 21.3, 14.0, 13.8.
FT-IR (cm-1): 1747, 1514, 1464, 1298, 1240, 1199, 1030, 1020.
11

MS (APCI): m/z = 423 [M(81Br) + H]+, 263 [M – Br2 + H]+, 217 [M – Br2 – C2H5O]+.
HRMS (APCI): m/z = 420.96445 [M + H]+; calcd. for C15H19O479Br2: 420.96446.
diethyl bromo(1-bromo-2-methylpropyl)malonate (5f)
Yield : 91%
Mol. formula: C11H18Br2O4
Mol. Wt. : 374.07 g.mol-1
Aspect: yellow oil
1H NMR (500 MHz, CDCl3): δ 4.70 (d, J = 3.0 Hz, 1H, HC-Br), 4.30 (q, J = 7.1 Hz, 4H, 2*CH2-CH3), 2.32 (dqq, J
= 6.6, 6.6, 3.0 Hz, 1H, HC-(CH3)2), 1.32 (t, J = 7.1 Hz, 3H, CH2-CH3), 1.31 (t, J = 7.1 Hz, 3H, CH2-CH3), 1.07 (d, J
= 6.7 Hz, 3H, HC(CH3)2), 1.06 (d, J = 6.4 Hz, 3H, HC(CH3)2).
13C NMR (125 MHz, CDCl3): δ 165.5, 164.5, 68.5, 63.9, 63.6, 62.7, 32.0, 23.3, 19.9, 14.0, 13.9.
FT-IR (cm-1): 2980, 2937, 2908, 2878, 1740, 1464, 1445, 1389, 1367, 1337, 1327, 1298, 1238, 1192, 1121, 1096,
1068, 1020, 991, 858.
MS (APCI): m/z = 375 [M (79Br81Br) + H]+, 329 [M (79Br81Br) – C2H5O]+.
HRMS (APCI): m/z = 372.96496 [M (79Br2) + H]+; calcd. for C11H19O479Br2: 372.96446.
triethyl 1,2-dibromoethane-1,1,2-tricarboxylate (5g)
Yield : 93%
Mol. formula: C11H16Br2O6
Mol. Wt. : 404.05 g.mol-1
Aspect: colorless liquid
1H NMR (300 MHz, CDCl3): δ 5.14 (s, 1H, HC-CO2Et), 4.41 – 4.24 (massif, 6H, 3*CH2-CH3), 1.38 – 1.30 (massif,
9H, 3*CH2-CH3).
13C NMR (75 MHz, CDCl3): δ 165.8, 164.5, 163.5, 64.0, 63.9, 62.9, 62.0, 46.4, 13.8, 13.8, 13.7.
12

FT-IR (cm-1): 2984, 2939, 2907, 1740, 1466, 1445; 1393, 1367, 1327, 1296, 1244, 1192, 1155, 1111, 1096, 1020,
914, 856, 731.
MS (APCI): m/z = 405 [M (79Br81Br) + H]+.
HRMS (APCI): m/z = 402.93892 [M (79Br2) + H]+; calcd. for C11H17O679Br2: 402.93864.
2.2.4. Elimination/Suzuki-Miyaura cross coupling
General procedure:
In a dry round bottom flask was added the compound 5a-d (2.4 mmol) and 20 mL CH2Cl2. Then DBU (3.5
mmol) was added, slowly, at 0 °C. After 20 min stirring at room temperature, the solution was diluted with H2O (10
mL), and then washed with HCl 1M solution (10 mL). The organic layer was dried over MgSO4, filtered and
concentrated under reduced pressure.
The residue (compound 6a-d) was then diluted with 20 mL EtOH, and potassium vinyltrifluoroborate (430
mg, 3.2 mmol), PdCl2dppf (90 mg, 0.12 mmol) and triethylamine (0.53 mL, 3.8 mmol) were added under inert
atmosphere. The reaction mixture was heated at 40°C for 16h and then concentrated under vacuum. The residue was
diluted with EtOAc (40 mL), washed with H2O (20 mL), NH4Clsat solution (20 mL), and brine (20 mL). The organic
layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by flash
chromatography with the appropriate mixture of cyclohexane and EtOAc.
diethyl (1-phenylprop-2-en-1-ylidene)malonate (7a)
Yield : 44%
Mol. formula: C16H18O4
Mol. Wt. : 274.31 g.mol-1
Aspect: yellow oil
1H NMR (500 MHz, CDCl3): δ 7.48 (dd, J = 17.2, 10.8 Hz, 1H, H2C=CH), 7.36 – 7.27 (massif, 3H, Ar), 7.16 (m,
2H, Ar), 5.60 (dd, J = 10.5, 1.5 Hz, 1H, HCH), 5.13 (dd, J = 17.3, 1.3 Hz, 1H, HCH), 4.28 (q, J = 7.2 Hz, 2H, H2C-
CH3), 3.89 (q, J = 7.2 Hz, 2H, H2C-CH3), 1.29 (t, J = 7.0 Hz, 3H, H2C-CH3), 0.89 (t, J = 7.0 Hz, 3H, H2C-CH3).
13

13C NMR (125 MHz, CDCl3): δ 165.7, 164.2, 153.0, 136.4, 134.8, 128.9, 128.4, 127.9, 127.6, 125.7, 61.3, 61.0,
14.1, 13.6.
FT-IR (cm-1): 1728, 1252, 1224, 1095, 1065, 1023, 701.
MS (APCI): m/z = 229 [M – C2H5O]+.
HRMS (APCI): m/z = 275.12773 [M + H]+; calcd. for C16H19O4: 275.12779.
diethyl [1-(4-chlorophenyl)prop-2-en-1-ylidene]malonate (7b)
Yield : 36%
Mol. formula: C16H17ClO4
Mol. Wt. : 308.76 g.mol-1
Aspect: yellow oil
1H NMR (500 MHz, CDCl3): δ 7.43 (dd, J = 17.5, 10.5 Hz, 1H, H2C=CH), 7.33 (massif, 2H, Ar), 7.12 (massif, 2H,
Ar), 5.63 (dd, J = 10.5, 1.0 Hz, 1H, HCH), 5.14 (dd, J = 17.5, 1.0 Hz, 1H, HCH), 4.31 (q, J = 7.2 Hz, 2H, H2C-CH3),
3.96 (q, J = 7.2 Hz, 2H, H2C-CH3), 1.33 (t, J = 7.0 Hz, 3H, H2C-CH3), 1.00 (t, J = 7.0 Hz, 3H, H2C-CH3).
13C NMR (125 MHz, CDCl3): δ 165.4, 164.3, 151.7, 134.8, 134.8, 134.6, 130.4, 128.3, 127.7, 126.2, 61.6, 61.3,
14.2, 13.8.
FT-IR (cm-1): 1732, 1715, 1614, 1582, 1487, 1464, 1445, 1393, 1367, 1325, 1300, 1215, 1178, 1124, 1088, 1061,
1028, 1014, 937, 833, 741.
MS (APCI): m/z = 309 [M(35Cl) + H]+, 263 [M(35Cl) – C2H5O]+.
HRMS (APCI): m/z = 309.08856 [M(35Cl) + H]+; calcd. for C16H18O435Cl: 309.08881.
diethyl [1-(4-fluorophenyl)prop-2-en-1-ylidene]malonate (7c)
Yield : 32%
Mol. formula: C16H17FO4
Mol. Wt. : 292.30 g.mol-1
Aspect: yellow oil
14

1H NMR (500 MHz, CDCl3): δ 7.44 (dd, J = 17.2, 10.6 Hz, 1H, H2C=CH-C), 7.16 – 7.11 (massif, 2H, Ar), 7.04 –
6.98 (massif, 2H, Ar), 5.59 (dd, J = 10.5, 1.2 Hz, 1H, HCH), 5.10 (dd, J = 17.1, 1.2 Hz, 1H, HCH), 4.26 (q, J = 7.1
Hz, 2H, H2C-CH3), 3.92 (q, J = 7.1 Hz, 2H, H2C-CH3), 1.28 (t, J = 7.2 Hz, 3H, H2C-CH3), 0.95 (t, J = 7.0 Hz, 3H,
H2C-CH3).
13C NMR (125 MHz, CDCl3): δ 165.6, 164.2, 162.8 (d, J = 246.4 Hz), 151.9, 134.9, 132.3 (d, J = 3.2 Hz), 130.8 (d,
J = 8.1 Hz), 127.6, 126.2, 115.1 (d, J = 21.5 Hz), 61.5, 61.1, 14.1, 13.7.
FT-IR (cm-1): 1716, 1614, 1603, 1576, 1504, 1466, 1446, 1367, 1323, 1250, 1228, 1200, 1159, 1122, 1095, 1059,
1030, 1014, 937, 864, 839, 820, 791.
MS (APCI): m/z = 293 [M + H]+, 247 [M – C2H5O]+.
HRMS (APCI): m/z = 293.11832 [M + H]+; calcd. for C16H18O4F: 293.11836.
diethyl [1-(4-methylphenyl)prop-2-en-1-ylidene]malonate (7d)
Yield : 16%
Mol. formula: C17H20O4
Mol. Wt. : 288.34 g.mol-1
Aspect: colorless oil
1H NMR (300 MHz, CDCl3): δ 7.47 (dd, J = 17.2, 10.6 Hz, 1H, H2C=CH=C), 7.14 (d, J = 8.1 Hz, 2H, Ar), 7.06 (d,
J = 8.1 Hz, 2H, Ar), 5.60 (dd, J = 10.6, 1.0 Hz, 1H, HCH), 5.17 (dd, J = 17.1, 0.9 Hz, 1H, HCH), 4.28 (q, J = 7.1 Hz,
2H, H2C-CH3), 3.93 (q, J = 7.1 Hz, 2H, H2C-CH3), 2.34 (s, 3H, H3C-Ar), 1.30 (t, J = 7.2 Hz, 3H, H2C-CH3), 0.95 (t,
J = 7.0 Hz, 3H, H2C-CH3).
13C NMR (75 MHz, CDCl3): δ 166.0, 164.5, 153.4, 138.4, 135.1, 133.6, 129.0, 128.7, 127.6, 125.6, 61.4, 61.1, 21.4,
14.2, 13.8.
FT-IR (cm-1): 2986, 1713, 1614, 1578, 1510, 1464, 1446, 1367, 1325, 1227, 1184, 1122, 1096, 1063, 1032, 820.
MS (ESI): m/z = 327 [M + K]+, 311 [M + Na]+, 289 [M + H]+, 243 [M – C2H5O]+.
HRMS (ESI): m/z = 289.14376 [M + H]+; calcd. for C17H21O4: 289.14344.
15

triethyl buta-1,3-diene-1,1,2-tricarboxylate (7g)
Yield : 47%
Mol. formula: C13H18O6
Mol. Wt. : 270.28 g.mol-1
Aspect: colorless liquid
1H NMR (500 MHz, CDCl3): δ 6.65 (dd, J = 17.5, 11.0 Hz, 1H, CH2=CH), 5.68 (d, J = 11.0 Hz, 1H, CH2=CH),
5.65 (d, J = 17.5 Hz, 1H, CH2=CH), 4.36 (q, J = 7.0 Hz, 2H, CH2-CH3), 4.33 (q, J = 7.0 Hz, 2H, CH2-CH3), 4.24 (q,
J = 7.0 Hz, 2H, CH2-CH3), 1.35 (t, J = 7.0 Hz, CH2-CH3), 1.33 (t, J = 7.0 Hz, CH2-CH3), 1.28 (t, J = 7.0 Hz, CH2-
CH3).
13C NMR (125 MHz, CDCl3): δ 166.1, 164.4, 163.1, 145.1, 129.7, 126.8, 125.4, 62.11, 62.06, 62.04, 14.19, 14.11,
14.09.
FT-IR (cm-1): 2984, 2962, 2926, 2905, 2872, 2853, 1724, 1620, 1595, 1466, 1447, 1391, 1367, 1319, 1298, 1244,
1182, 1163, 1096, 1068, 1024, 943, 862, 800, 779, 719.
MS (APCI): m/z = 271 [M + H]+, 215 [M – C2H5O]+.
HRMS (APCI): m/z = 271.11734 [M + H]+; calcd. for C13H19O6: 271.11761.
2.2.5. Michael addition
General Procedure
In a dry round bottom flask was added CuI (2.8 mmol) and 20 mL of THF under inert atmosphere. A 0.5829
M solution of vinylmagnesiumbromide in THF (10.1 mL; 5.9 mmol) was next added dropwise at 0 °C; the reaction
mixture was stirred 45 min at this temperature. A solution of compound 4 (2.3 mmol) in 20 mL of THF was next
added dropwise at -78 °C. The reaction mixture was stirred overnight (the cooling bath recovering slowly to room
temperature). The reaction was then quenched with a NH4Clsat solution (5 mL), then diluted with water (10 mL) and
Et2O (50 mL). After layer separation, the aqueous layer was extracted with Et2O (2x 30 mL). The combined organic
layers was washed with brine, dried over MgSO4, and finally concentrated under vacuum. The residue was purified
by flash chromatography (10/90 EtOAc/cyclohexane) to give the desired product.
16

diethyl [1-(4-methoxyphenyl)prop-2-en-1-yl]malonate (8e)
CAS Reg. No. 1127889-64-8
Yield : 48%
Mol. formula: C17H22O5
Mol. Wt. : 306.35 g.mol-1
Aspect: pale yellow liquid
1H NMR (500 MHz, CDCl3): δ 7.15 (m, 2H, Ar), 6.83 (m, 2H, Ar), 5.97 (ddd, J = 17.1, 10.2, 8.0 Hz, 1H,
CH2=CH), 5.09 (dd, J = 17.1, 1.2 Hz, 1H, CH2=CH), 5.05 (dd, J = 10.2, 1.0 Hz, 1H, CH2=CH), 4.20 (q, J = 7.1 Hz,
2H, CH2-CH3), 4.06 (dd, J = 11.1, 8.1 Hz, 1H, HC-Ar), 3.95 (m, 2H, CH2-CH3), 3.78 (d, J = 11.1 Hz, 1H,
HC(CO2Et)2), 3.77 (s, 3H, O-CH3), 1.27 (t, J = 7.1 Hz, 3H, CH2-CH3), 1.02 (t, J = 7.1 Hz, 3H, CH2-CH3).
13C NMR (125 MHz, CDCl3): δ 168.0, 167.7, 158.7, 138.4, 132.2, 129.2, 116.2, 114.1, 61.6, 61.4, 57.7, 55.4, 49.0,
14.2, 14.0.
FT-IR (cm-1): 2982, 2935, 2907, 2361, 2338, 1753, 1730, 1637, 1610, 1583, 1512, 1464, 1445, 1391, 1367, 1302,
1246, 1176, 1157, 1144, 1124, 1095, 1034, 993, 922, 829, 658.
MS (APCI): m/z = 307 [M + H]+, 147 [M – C7H11O4]+.
HRMS (APCI): m/z = 307.15391 [M + H]+; calcd. for C17H23O5: 307.15400.
diethyl (1-isopropylprop-2-en-1-yl)malonate (8f)
CAS Reg. No. 908102-65-8
Yield : 65%
Mol. formula: C13H22O4
Mol. Wt. : 242.31 g.mol-1
Aspect: pale yellow liquid
1H NMR (500 MHz, CDCl3): δ 5.69 (ddd, J = 17.0, 10.1, 10.1 Hz, 1H, CH2=CH, 2), 5.10 (dd, J = 10.3, 2.0 Hz, 1H,
CH2=CH, 1), 5.06 (dd, J = 17.0, 1.9 Hz, 1H, CH2=CH, 1), 4.22 – 4.12 (massif, 4H, 2*CH2-CH3, 9 and 12), 3.53 (d, J
= 9.7 Hz, 1H, CH-(CO2Et)2, 7), 2.65 (ddd, J = 9.7, 9.7, 4.9 Hz, CH-(i-Pr), 3), 1.75 (m, 1H, CH-(CH3)2, 4), 1.26 (t, J
= 7.2 Hz, CH2-CH3, 10 or 13), 1.24 (t, J = 7.2 Hz, CH2-CH3, 13 or 10), 0.91 (d, J = 6.8 Hz, 3H, CH-(CH3)2, 5 or 6),
0.84 (d, J = 6.9 Hz, 3H, CH-(CH3)2, 6 or 5).
17

13C NMR (125 MHz, CDCl3): δ 168.8 ;168.5 (8,11), 135.0 (2), 118.8 (1), 61.5 ;61.3 (9,12), 55.1 (7), 50.4 (3), 29.1
(4), 21.4 ;17.7 (5,6), 14.2 (10,13).
FT-IR (cm-1): 2974, 2961, 2934, 2905, 2874, 1755 (C=O), 1732 (C=O), 1639 (C=C), 1466, 1447, 1389, 1369, 1323,
1300, 1259, 1242, 1227, 1178, 1144, 1132, 1096, 1034, 1003, 920.
MS (APCI): m/z = 243 [M + H]+, 197 [M – C2H5O]+.
HRMS (APCI): m/z = 243.15893 [M + H]+; calcd. for C13H23O4: 243.15909.
diethyl (1-butylprop-2-en-1-yl)malonate (8h)
CAS Reg. No. 117749-06-1
Yield : 96%
Mol. formula: C14H24O4
Mol. Wt. : 256.34 g.mol-1
Aspect: orange liquid
1H NMR (300 MHz, CDCl3): δ 5.64 (ddd, J = 17.0, 10.2, 9.4 Hz, 1H, CH2=CH), 5.10 – 5.04 (massif, 2H,
CH2=CH), 4.19 (q, J = 7.1 Hz, 2H, O-CH2-CH3), 4.14 (q, J = 7.1 Hz, 2H, O-CH2-CH3), 3.33 (d, J = 8.9 Hz, 1H,
HC(CO2Et)2), 2.75 (ddt, 9.1, 9.1, 3.4 Hz, 1H, HC-(n-Bu)), 1.37 – 1.14 (massif, 6H, (CH2)3-CH3), 1.26 (t, J = 7.1 Hz,
3H, O-CH2-CH3), 1.24 (t, J = 7.1 Hz, 3H, O-CH2-CH3).
13C NMR (125 MHz, CDCl3): δ 168.6, 168.4, 138.4, 117.4, 61.4, 61.3, 57.2, 44.2, 32.1, 29.3, 22.6, 14.3, 14.1.
FT-IR (cm-1): 2982, 2957, 2934, 2907, 2874, 2860, 2365, 2341, 2316, 1751, 1732, 1641, 1466, 1447, 1391, 1369,
1300, 1263, 1242, 1223, 1176, 1144, 1095, 1034, 918.
MS (APCI): m/z = 257 [M + H]+, 211 [M – C2H5O]+.
HRMS (APCI): m/z = 257.17464 [M + H]+; calcd. for C14H25O4: 257.17474.
2.2.6. Double bond reformation
18

General Procedure
In a dry round bottom flask was added compound 8 (1 mmol) in 5 mL of DMF under inert atmosphere. NaH
(60% dispersion in mineral oil; 1.2 mmol) was then added at 0°C. The mixture was stirred for 1h at room
temperature (= solution A).
In another dry round bottom flask was added PhSeCl (2 mmol) in 5 mL of DMF. This solution was cooled
to -10°C, and then added, very slowly (over 2h), to solution A. This mixture was stirred for two more hours at -10°C
and then for 2h at 0°C. Finally H2O2 (30% sol. in water; 15 mmol) was added, at 0 °C. The solution was stirred for
30 min at this temperature. The reaction was then quenched with a NaHCO3sat solution (5 mL), diluted with water
(20 mL) and extracted with EtOAc (2*20 mL). The combined organic layers were washed with water (10 mL), brine
(10 mL), dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by flash
chromatography (05/95 => 10/90 EtOAc/cyclohexane) to give the desired product.
diethyl [1-(4-methoxyphenyl)prop-2-en-1-ylidene]malonate (7e)
Yield : 47%
Mol. formula: C17H20O5
Mol. Wt. : 304.34 g.mol-1
Aspect: pale yellow liquid
1H NMR (300 MHz, CDCl3): δ 7.47 (dd, J = 17.2, 10.5 Hz, 1H, CH2=CH), 7.17 – 7.08 (m, 2H, Ar), 6.92 – 6.83 (m,
2H, Ar), 5.62 (dd, J = 10.5, 1.4 Hz, 1H, CH2=CH), 5.21 (dd, J = 17.2, 1.4 Hz, CH2=CH), 4.29 (q, J = 7.1 Hz, 2H,
CH2-CH3), 3.96 (q, J = 7.1 Hz, 2H, CH2-CH3), 3.81 (s, 3H, O-CH3), 1.31 (t, J = 7.1 Hz, 3H, CH2-CH3), 0.99 (t, J =
7.1 Hz, 3H, CH2-CH3).
13C NMR (75 MHz, CDCl3): δ 166.2, 164.5, 159.9, 153.2, 135.4, 130.5, 128.8, 127.5, 125.5, 113.5, 61.4, 61.1, 55.4,
14.2, 13.8.
FT-IR (cm-1): 2980, 2964, 2937, 2907, 2837, 1717, 1609, 1578, 1510, 1464, 1445, 1404, 1391, 1367, 1327, 1306,
1292, 1248, 1215, 1176, 1124, 1113, 1095, 1063, 1030, 939, 862, 835, 812, 797, 783.
MS (APCI): m/z = 305 [M + H]+, 259 [M – C2H5O]+.
HRMS (APCI): m/z = 305.13827 [M + H]+; calcd. for C17H21O5: 305.13835.
19

diethyl (1-isopropylprop-2-en-1-ylidene)malonate (7f)
Yield : 36%
Mol. formula: C13H20O4
Mol. Wt. : 240.30 g.mol-1
Aspect: pale yellow liquid
1H NMR (300 MHz, CDCl3): δ 6.42 (dd, J = 17.7, 11.7 Hz, 1H, CH2=CH), 5.31 (dd, J = 17.7, 1.5 Hz, 1H,
CH2=CH), 5.27 (dd, J = 11.7, 1.5 Hz, 1H, CH2=CH), 4.17 (q, J = 7.2 Hz, 2H, CH2-CH3), 4.12 (q, J = 7.2 Hz, 2H,
CH2-CH3), 3.32 (sep, J = 6.9 Hz, 1H, CH-(CH3)2), 1.22 (t, J = 7.3 Hz, 3H, CH2-CH3), 1.20 (t, J = 7.3 Hz, 3H, CH2-
CH3), 1.03 (d, J = 6.9 Hz, 6H, CH-(CH3)2).
13C NMR (75 MHz, CDCl3): δ 166.2, 165.0, 161.3, 132.6, 124.2, 120.9, 61.1, 30.9, 20.9, 14.1, 14.0.
FT-IR (cm-1): 2980, 2936, 2907, 2874, 1721, 1615, 1580, 1466, 1447, 1418, 1387, 1366, 1337, 1298, 1285, 1269,
1219, 1204, 1160, 1096, 1061, 1025, 934, 868, 791, 733.
MS (APCI): m/z = 241 [M + H]+, 195 [M – C2H5O]+.
HRMS (APCI): m/z = 241.14322 [M + H]+; calcd. for C13H21O4: 241.14344.
diethyl (1-butylprop-2-en-1-ylidene)malonate (7h)
Yield : 35%
Mol. formula: C14H22O4
Mol. Wt. : 254.32 g.mol-1
Aspect: yellow liquid
1H NMR (300 MHz, CDCl3): δ 6.93 (dd, J = 17.4, 11.0 Hz, 1H, CH2=CH), 5.70 (d, J = 17.4 Hz, 1H, CH2=CH),
5.50 (d, J = 11.0 Hz, 1H, CH2=CH), 4.23 (q, J = 7.1 Hz, 4H, 2*CH2-CH3), 2.55 (m, 2H, CH2-(n-prop)), 1.53 – 1.20
(massif, 4H, (CH2)2-CH3), 1.28 (t, J = 7.1 Hz, 6H, 2*O-CH2-CH3), 0.90 (t, J = 7.1 Hz, 3H, CH3-(CH2)3-C).
13C NMR (75 MHz, CDCl3): δ 165.6, 165.5, 153.7, 133.8, 125.3, 122.2, 61.3, 61.1, 31.9, 29.2, 23.2, 14.2, 13.9.
FT-IR (cm-1): 2978, 2959, 2933, 2907, 2872, 1717, 1620, 1583, 1464, 1447, 1389, 1366, 1300, 1279, 1223, 1198,
1115, 1096, 1061, 1030, 932, 868, 791, 733.
20

MS (APCI): m/z = 255 [M + H]+, 209 [M – C2H5O]+.
HRMS (APCI): m/z = 255.15882 [M + H]+; calcd. for C14H23O4: 255.15909.
21