Palladium- and norbornene-catalyzed synthesis of highly functionalized thiophenes: The remarkable effect of electron-poor olefins as ligand

Article abstract of DOI:10.3987/COM-16-S(S)78

Highly functionalized heterocyclic compounds were synthesized by palladium and norbornene catalysis starting from ortho-substituted aryl iodides, aryl bromides and 3,4-ethylenedioxythiophene. The addition of methyl cinnamate to the reaction mixture was fo

Full text of DOI:10.3987/COM-16-S(S)78

SUPPORTING INFORMATION
PALLADIUM- AND NORBORNENE- CATALYZED SYNTHESIS OF
HIGHLY FUNCTIONALIZED THIOPHENES: THE REMARKABLE
EFFECT OF ELECTRON-POOR OLEFINS AS LIGAND
Nicola Della Ca’,1* Elena Motti,1 Giovanni Maestri,1,2 and Max Malacria2*
1 Dipartimento di Chimica and CIRCC, Università di Parma, Parco Area delle Scienze, 17/A,
43124 Parma, Italy. 2 ICSN CNRS UPR2301, 1 Av. de la Terrasse, Bat. 27, 91198 Gif s/Yvette,
France. 3 UPMC Sorbonne Université, IPCM UMR CNRS 8232, 4 place Jussieu, C. 229, 75005
Paris, France. e-mail: nicola.dellaca@unipr.it ; max.malacria@cnrs.fr.
Contents
General remarks
S2
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S3
S8
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General procedure for the synthesis of compounds 1
Product characterizations
References
NMR spectra
S1

General remarks
Most reagents were obtained from commercial sources and used as received. 2-i-Propyliodobenzene
was prepared starting from the corresponding aniline derivative by diazotization procedure.1 DMF
was dried and stored over 4 Å molecular sieves under nitrogen. Reactions were carried out under
nitrogen using standard Schlenk technique. Gas chromatography analyses were performed with a
Carlo Erba HRGC 5300 instrument using a 30 m SE-30 capillary column. Flash column
chromatography was performed on Merck Kieselgel 60 and thin-layer chromatography on Merck
60F254 plates. Melting points were determined with an Electrothermal apparatus and are uncorrected.
1H NMR and 13C NMR spectra were recorded at 293 K, in CDCl3 on Bruker AC-300 and
1
13
AVANCE 300 spectrometers at 300.1 and 75.4 MHz respectively. H and C chemical shifts are
1
reported relative to TMS and were determined by reference to residual H and 13C solvent
resonances. The reported assignments are based on decoupling, COSY, NOESY, C–H HSQC,
HMBC correlation experiments. GCMS spectra (EI, 70eV) were performed on a Hewlett Packard
HP 6890 GC system equipped with a SE-52 capillary column and a HP5973 Mass Selective
Detector mass analyzer. Elemental analyses were performed with a Carlo Erba EA 1108-Elemental
Analyzer.
General procedure for the reaction of an ortho-substituted aryl iodide, an aryl bromide and 3,4-
ethylenedioxythiophene
The ortho-substituted aryl iodide (0.36 mmol), the desired aryl bromide (0.36 mmol), 3,4-
ethylenedioxythiophene (127 mg, 0.9 mmol), norbornene (34 mg, 0.36 mmol), Pd(OAc)2 (4 mg,
0.018 mmol), methyl cinnamate (233 mg, 1.44 mmol) and K2CO3 (0.11 g, 0.8 mmol) in DMF (8
mL) were stirred in a Schlenk-type flask under nitrogen with a magnetic bar at 105 ˚C for 24–96 h.
At the end of the reaction the mixture was allowed to cool to room temperature, diluted with EtOAc
(30 mL), washed three times with brine (3 × 30 mL) and dried over Na2SO4. The solvent was
1
removed under reduced pressure and the crude mixture was analyzed by GC and H NMR
spectroscopy. The products were isolated by flash column chromatography on silica gel using a
mixture of hexane-EtOAc as eluent.
S2

Product characterizations
2-(3,2'-Di-i-propyl-1,1'-biphenyl-2-yl)-3,4-ethylenedioxythiophene (3a)
i-Pr
i-Pr
S
O
O
Compound 3a was previously characterized2 as follows: the crude product was purified by flash
chromatography on silica gel (hexane:ethylacetate = 95:5) to give the title compound as a pale
yellow solid. M.p. (hexane): 130–131.5 ºC. A 4:3 mixture of two stereoisomers indicated as A and
B. 1H NMR:  7.47–7.40 (4H, m, (A, B)), 7.32–7.12 (9H, m, (4H for A, 5H for B)), 7.05 (1H, ddd,
J = 7.8, 6.6, 1.9 Hz, A), 6.24, 6.18 (2H, 2 s, (B, A)), 4.20–3.96 (8H, m, (4H for A, 4H for B)), 3.11,
3.09 (2H, 2 hept, J = 6.9 Hz, (A, B)), 2.90, 2.86 (2H, 2 hept, J = 6.9 Hz, (B, A)), 1.37 (3H, d, J =
6.9 Hz, B), 1.30, 1.29 (6H, 2 d, J = 6.9 Hz, A), 1.22 (3H, d, J = 6.9 Hz, A), 1.21 (3H, d, J = 6.9 Hz,
B), 1.20 (3H, d, J = 6.9 Hz, A), 1.12, 1.09 (6H, 2 d, J = 6.9 Hz, B). 13C NMR:  150.2, 149.7, 146.7,
146.1, 143.7, 143.4, 140.5, 140.3, 140.21, 140.19, 138.1, 137.7, 130.7, 129.6, 129.2, 129.1, 128.1,
128.0, 127.6, 127.4, 127.23, 127.19, 124.6, 124.5, 124.2, 124.1, 124.0, 123.9, 114.6, 99.0, 98.0,
64.4, 64.22, 64.18, 30.6, 30.4, 29.8, 29.4, 25.6, 25.3, 24.8, 24.3, 24.1, 23.5, 23.0, 22.9. MS: M+ 378
(100), m/z 335 (53), 287 (20), 261 (15), 221 (18), 202 (24), 189 (17), 178 (12), 165 (15). Anal.
Calcd. for C24H26O2S: C, 76.15; H, 6.92; O, 8.45; S, 8.47. Found: C, 76.07; H, 6.94.
2-(3,2'-Dicarbomethoxy-1,1'-biphenyl-2-yl)-3,4-ethylenedioxythiophene (4a)
MeO2C
MeO2C
S
O
O
Compound 4a was previously characterized2 as follows: the crude product was purified by flash
chromatography on silica gel (hexane:ethylacetate = 7:3) to give the title compound as a pale
yellow solid. M.p. (hexane): 88–89 ºC. 1H NMR:  7.86–7.81 (2H, m), 7.48–7.39 (3H, m), 7.32 (1H,
td, J = 7.6, 1.5 Hz), 7.21 (1H, br d, J = 7.5 Hz), 6.17 (1H, s), 4.08–3.75 (4H, m), 3.72 (3H, s), 3.59
13
(3H, s). C NMR:  168.2, 167.1, 144.5, 141.6, 140.2, 138.0, 133.1, 132.3, 131.3, 130.8, 130.0,
S3

129.8, 129.7, 128.7, 127.5, 127.2, 113.6, 99.5, 64.2, 52.0, 51.6. MS: M+ 410 (100), m/z 351 (29), 59
(10). Anal. Calcd. for C22H18O6S: C, 64.38; H, 4.42; O, 23.39; S, 7.81. Found: C, 64.27; H, 4.46.
2’-(2’’-Carbomethoxy-3’-i-propyl-1’,1’’-biphenyl-2’-yl)-3,4-ethylenedioxythiophene (1a)
The crude product was purified by flash chromatography on silica gel (hexane:ethylacetate = 8:2) to
give the title compound (92 mg, 65% yield) as a pale yellow oil.
1
A 2:1 mixture of stereoisomers indicated as A and B. H NMR:  7.86–7.82 (2H, m, H3”), 7.45–
7.34 (6H, m, H6”, H4’, H5”), 7.32–7.25 (2H, m, H4”), 7.24–7.17 (2H, m, H5’), 7.09–7.02 (2H, m,
H6’), 6.15 (1H, s, H5A), 6.14 (1H, s, H5B), 4.14–3.76 (8H, m, 2H3 and 2H4 (4H for A, 4H for B)),
3.62 (3H, s, CO2CH3 A), 3.54 (3H, s, CO2CH3 B), 3.06 (2H, hept, J = 6.8 Hz), 1.26 (3H, d, J = 6.8
Hz, CH(CH3)2), 1.24, 1.23 (6H, 2 d, J = 6.8 Hz, CH(CH3)2), 1.18 (3H, d, J = 6.8 Hz, CH(CH3)2 ).
13C NMR:  167.7 (CO B), 167.5 (CO A), 149.5 (C3’ A), 149.3 (C3’B), 144.1 (C2” A), 143.9 (C2”
B), 143.1 (C1”A), 142.9 (C1” B), 140.5 (C2a B), 140.3 (C2a A), 138.2 (C4a B), 137.9 (C4a A),
131.4 (C4” B), 130.9 (C4”A), 130.6 (C5”B), 130.3 (C5”A), 130.1(C1’* B), 129.73 (C1’* A),
129.69 (C3” B), 129.4 (C3” A), 128.7 (C2’*B) , 128.2 (C6” A), 127.9 (C2’* A), 127.7 (C6” B),
126.7 (C5’A), 126.63 (C6’ B), 126.58 ((C5’B), 125.9 (C6’A), 124.1 (C4’A), 124.0 (C4’B), 114.5
(C2 A), 114.1 (C2 B), 98.9 (C5 B), 98.4 (C5 A), 64.3 (C3, C4 B), 64.1 (C3, C4 A), 51.5 (CO2CH3
A), 51.3 (CO2CH3 B), 30.35 (CH(CH3)2 A) , 30.33 (CH(CH3)2 B), 24.5, 24.3, 23.9 (CH(CH3)2 A and
B; 2C overlapping in 23.9 ppm signal). MS: M+ 394 (100), m/z 335 (24), 317 (18), 259 (16), 202
(19), 189 (18), 59 (6). Anal. Calcd. for C23H22O4S: C, 70.03; H, 5.62; O, 16.22; S, 8.13. Found: C,
69.91; H, 5.67.
2-(3'-Carbomethoxy-3-i-propyl-1,1'-biphenyl-2-yl)-3,4-ethylenedioxythiophene (1b)
S4

CO2Me
i-Pr
S
O
O
The crude product was purified by flash chromatography on silica gel (hexane:ethylacetate = 8:2) to
1
give the title compound (83 mg, 59% yield) as a pale yellow oil. H NMR:  7.97 (1H, t, J = 2.0
Hz), 7.88 (1H, dt, J = 7.7, 1.6 Hz), 7.47–7.37 (3H, m), 7.30 (1H, t, J = 7.9 Hz), 7.22 (1H, d, J = 6.1,
2.6 Hz), 6.21 (1H, s), 4.18–3.79, 3.88 (4H, m + 3H, s), 3.15 (1H, hept, J = 6.9 Hz), 1.24, 1.23 (6H,
two partly overlapping d, J = 6.9 Hz). 13C NMR:  167.0, 150.3, 143.2, 142.4, 140.8, 138.9, 133.2,
130.3, 129.2, 129.0, 128.4, 127.5, 127.4, 127.0, 124.9, 114.2, 98.8, 64.4, 64.3, 51.9, 30.5, 24.4, 24.0.
MS: M+ 394 (100), m/z 349 (18), 295 (23), 221 (20), 202 (37), 189 (40), 165 (19), 59 (30). Anal.
Calcd. for C23H22O4S: C, 70.03; H, 5.62; O, 16.22; S, 8.13. Found: C, 70.12; H, 5.69.
2-(4'-Carbomethoxy-3-i-propyl-1,1'-biphenyl-2-yl)-3,4-ethylenedioxythiophene (1c)
CO2Me
i-Pr
S
O
O
The crude product was purified by flash chromatography on silica gel (hexane:ethylacetate = 8:2) to
1
give the title compound (0.110 g, 78% yield) as a pale yellow oil. H NMR:  7.93–7.87 (2H, m),
7.48–7.39 (2H, m), 7.33–7.25 (2H, m), 7.24–7.17 (1H, m), 6.23 (1H, s), 4.13–3.90 (3H, m), 3.89
(3H, s), 3.65 (1H, ddd, J = 11.4, 6.9, 1.8 Hz), 3.18 (1H, hept, J = 6.9 Hz), 1.23 (6H, t, J = 7.1 Hz).
13C NMR:  167.1, 150.2, 147.2, 143.1, 140.8, 138.7, 128.9, 128.6, 128.2, 127.9, 127.0, 125.2,
114.1, 98.8, 64.4, 64.2, 51.9, 30.4, 24.5, 24.0. MS: M+ 394 (100), m/z 349 (23), 334 (18), 295 (34),
260 (19), 221 (36), 202 (69), 189 (79), 178 (22), 165 (39), 59 (68). Anal. Calcd. for C23H22O4S: C,
70.03; H, 5.62; O, 16.22; S, 8.13. Found: C, 69.87; H, 5.56.
2-(3-i-Propyl-3'-trifluoromethyl-1,1'-biphenyl-2-yl)-3,4-ethylenedioxythiophene (1d)
S5

CF3
i-Pr
S
O
O
The crude product was purified by flash chromatography on silica gel (hexane:ethylacetate = 8:2) to
1
give the title compound (107 mg, 74% yield) as a pale yellow oil. H NMR:  7.60–7.57 (1H, m),
7.53–7.34 (5H, m), 7.28–7.13 (1H, m), 6.27 (1H, s), 4.19–4.05 (2H, m), 4.01–3.92 (1H, m), 3.81–
3.72 (1H, m), 3.22 (1H, hept, J = 6.8 Hz), 1.28, 1.26 (6H, two partly overlapping d, J = 6.8 Hz). 13C
NMR:  150.4, 143.0, 142.8, 140.9, 138.8, 132.1, 129.0, 127.9 (q, CCF3, J = 31.2 Hz), 127.7, 126.9,
126.0 (q, JC,F = 4.0 Hz), 125.2, 124.3 (q, CF3, JC,F = 273.0 Hz), 123.0 (q, JC,F = 4.0 Hz), 114.0, 98.9,
64.3, 64.2, 30.5, 24.4, 24.0. MS: M+ 404 (100), m/z 359 (28), 344 (21), 305 (35), 259 (26), 233 (29),
202 (24), 189 (25), 69 (8). Anal. Calcd. for C22H19F3O2S: C, 65.33; H, 4.74; F, 14.09; O, 7.91; S,
7.93. Found: C, 65.25; H, 4.69.
2-(3-i-Propyl-4'-trifluoromethyl-1,1'-biphenyl-2-yl)-3,4-ethylenedioxythiophene (1e)
CF3
i-Pr
S
O
O
The crude product was purified by flash chromatography on silica gel (hexane:ethylacetate = 8:2) to
1
give the title compound (93 mg, 64% yield) as a colourless oil. H NMR:  7.54–7.43 (4H, m),
7.37–7.31 (2H, m), 7.24–7.18 (1H, m), 6.28 (1H, s), 4.15–3.98 (2H, m), 3.92 (1H, ddd, J = 11.3, 5.2,
1.8 Hz), 3.67 (1H, ddd, J = 11.4, 6.5, 1.8 Hz), 3.21 (1H, hept, J = 6.9 Hz), 1.27, 1.24 (6H, two
partly overlapping d, J = 6.9 Hz). 13C NMR:  150.3, 146.0, 142.8, 140.9, 138.7, 129.2 (2C), 129.0,
127.2 (q, CCF3, J = 30.9 Hz), 127.1, 125.3, 124.3 (q, CF3, JC,F = 268.9 Hz), 124.1 (q, 2C, JC,F = 3.4
Hz), 114.0, 98.9, 64.4, 64.2, 30.4, 24.5, 24.0. MS: M+ 404 (100), m/z 359 (33), 344 (22), 305 (32),
259 (27), 233 (26), 202 (23), 189 (22), 69 (10). Anal. Calcd. for C22H19F3O2S: C, 65.33; H, 4.74; F,
14.09; O, 7.91; S, 7.93. Found: C, 65.21; H, 4.78.
2-(2'-Carbomethoxy-3-trifluoromethyl-1,1'-biphenyl-2-yl)-3,4-ethylenedioxythiophene (1f)
S6

MeO2C
CF3
O
S
O
The crude product was purified by flash chromatography on silica gel (hexane:ethylacetate = 8:2) to
give the title compound (101 mg, 67% yield) as a white solid. M.p. (hexane): 113–114 ºC. A 2:1
1
mixture of stereoisomers indicated as A and B. H NMR:  7.96–7.87 (2H, m, 1H (A), 1H (B)),
7.83–7.73 (2H, m, 1H (A), 1H (B)), 7.59–7.28 (8H, m, 4H (A), 4H (B)), 7.24 (1H, dd, J = 7.5, 1.5
Hz, A), 7.12 (1H, dd, J = 7.5, 1.5 Hz, B), 6.17 (2H, s, 1H (A), 1H (B)), 4.13–3.81 (8H, m, 4H (A),
13
4H (B)), 3.66 (3H, s, A), 3.58 (3H, s, B). C NMR:  167.2, 167.1, 146.9, 146.5, 141.5, 141.0,
140.2, 139.9, 139.2, 139.0, 133.1, 132.1, 131.5, 131.3, 131.0, 130.9, 130.7, 130.1, 130.0 (q, CCF3, J
= 31.1 Hz), 129.9, 129.7, 129.4, 128.2, 127.6, 127.5, 125.2, 125.1 (q, JC,F = 5.4 Hz), 123.9 (q, 2CF3,
JC,F = 272.3 Hz), 111.2, 111.0, 99.9, 99.7, 64.42, 64.39, 64.2, 51.9, 51.7. MS: M+ 420 (100), m/z
361 (40), 289 (18), 264 (17), 233 (19), 232 (18), 182 (13), 59 (8). Anal. Calcd. for C21H15F3O4S: C,
60.00; H, 3.60; F, 13.56; O, 15.22; S, 7.63. Found: C, 59.89; H, 3.65.
2-(4'-Carbomethoxy-3-trifluoromethyl-1,1'-biphenyl-2-yl)-3,4-ethylenedioxythiophene (1g)
CO2Me
CF3
O
S
O
The crude product was purified by flash chromatography on silica gel (hexane:ethylacetate = 8:2) to
give the title compound (94 mg, 62% yield) as a white solid. M.p. (hexane): 131–132 ºC. 1H NMR:
 7.96–7.89 (2H, m), 7.84–7.75 (1H, m), 7.62–7.53 (2H, m), 7.32–7.23 (2H, m), 6.28 (1H, s), 4.15–
3.92 (3H, m), 3.91 (3H, s), 3.73–3.66 (1H, m). 13C NMR:  166.9, 145.5, 145.2, 140.3, 139.6, 133.0,
131.7 (q, CCF3, J = 30.9 Hz), 130.7 (q, JC,F = 5.2 Hz), 128.84 (2C), 128.80 (2C), 128.76, 128.7,
125.9 (q, JC,F = 5.3 Hz), 123.7 (q, CF3, JC,F = 258.7 Hz), 110.8, 100.1, 64.34, 64.30, 52.1. MS: M+
420 (100), m/z 355 (20), 232 (14), 59 (7). Anal. Calcd. for C21H15F3O4S: C, 60.00; H, 3.60; F,
13.56; O, 15.22; S, 7.63. Found: C, 60.15; H, 3.57.
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References
(1)
(2)
M. S. Lesslie and U. J. H. Mayer, J. Chem. Soc., 1961, 611–618.
N. Della Ca’, G. Maestri and Marta Catellani, Chem. Eur. J., 2009, 15, 7850.
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