Les résultats de ces travaux de recherche nous ont permis de développer des réactions de Friedel-crafts à partir de fluorures de benzyles dans des conditions plus douces que les précédents de la littérature. Nous avons également mis en évidence le rôle du HFIP dans l’activation de liaisons C-F, ce qui nous a permis de tester la réaction sur une large étendue, tout cela accompagné de résultats qui confirment nos hypothèses concernant l'activation du lien C-F.
De façon générale, nous avons démontré qu'avec nos conditions, nous avons pu accéder à des composés de type 1,1-diarylalcanes sans la nécessité d'un métal de transition ou d'un acide de Lewis fort. Ce mode d'activation permet une réaction sélective de la liaison benzylique C-F en présence d'autres groupements partants benzyliques (Cl, Br).
Ce projet a également ouvert d'autres perspectives à explorer, comme par exemple tester les mêmes conditions sur les alcools benzyliques et qui ont donné des résultats très concluants.
L'étude approfondie de plusieurs autres domaines qui pourraient bénéficier de cette nouvelle réactivité reste à explorer pour l'avenir tel que par exemple l'optimisation de nouvelles réactions avec des fluorures d'alkyle, d'allyle ou d'acyle.
SUPPLEMENTARY INFORMATION
Friedel-Crafts Reaction of Benzyl Fluorides: Selective Activation of C-F
Bonds Enabled by Hydrogen-Bonding
General information
Unless otherwise noted, all commercial reagents were used without further purification. Dichloromethane, toluene, tetrahydrofuran and acetonitrile were purified using a Vacuum Atmospheres Inc. Solvent Purification System. Thin-layer chromatography (TLC) analysis of reaction mixtures was performed using Silicyle silica gel 60 Å F254 TLC plates, and visualized under UV or by staining with iodine. Flash column chromatography was carried out on Silicycle Silica Gel 60 Å, 230 X 400 mesh. High-resolution mass spectra were obtained on a LC/MS-TOF Agilent 6210 using either electrospray ionization (ESI) or atmospheric pressure photoionization (APPI). 1H, 13C {1H}, 19F and 11B {1H} nuclear
magnetic resonance (NMR) spectra were recorded using Agilent DD2 500 and Varian Inova 400 spectrometers. 1H and 13C chemical shifts are reported in ppm downfield of
tetramethylsilane and referenced to tetramethylsilane (δ = 0 ppm) or residual chloroform peak (δ = 7.26 ppm). For 19F NMR, CFCl
3 is used as the external standard and for 11B
{1H}, reference is external B(OMe)
3. Coupling constants (J) are measured in hertz (Hz).
Multiplicities are reported using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad resonance. Infrared spectra were recorded using a Thermo Scientific Nicolet 380 FT-IR spectrometer. Melting points were recorded on a Stanford ResearchSystem OptiMelt capillary melting point apparatus and are uncorrected. When Friedel-Crafts products were obtained as a solid mixture of regioisomers, no melting points were measured. When possible, NMR assignment for peaks of the different isomers is given.
Materials and methods
General procedures for the synthesis of fluorinated substrates
Nucleophilic fluorination of benzylic bromides general procedure (Procedure A):
To a stirred solution of the benzylic bromide (1 equiv.) in anhydrous acetronitrile (0.5 M) was added tetrabutylammonium fluoride trihydrate (2 equiv.). The reaction mixture was stirred 18 h at room temperature. The reaction was quenched with water and extracted with Et2O (3x). The combined organic extracts were washed with brine, dried with MgSO4,
filtered and concentrated under vacuum. Column chromatography followed. Deoxofluorination general procedure (Procedure B):
For several substrates, a benzylic alcohol is directly fluorinated using this procedure, which is a variation of a known protocol
In a round-bottomed flask, to CH2Cl2 (one third of what is necessary for 0.2 M) is added
(dimethylamino)sulfur trifluoride (Me-DAST, 1-2 equiv.) and the solution was cooled to - 78 °C, upon which 4-(trimethylsilyl)morpholine (1.1-2.2 equiv.) was added. The mixture was allowed to heat to room temperature and stirred for 2.5 hours. This solution was cooled again to -78 °C and a solution of the alcohol (1 equiv.) in the two thirds of CH2Cl2 (total:
0.2 M) was added dropwise. The mixture was again allowed to reach room temperature and was stirred for 16 hours, at which point it was quenched by slowly adding 1 mL MeOH, then a saturated aqueous NaHCO3 solution. The aqueous mixture was extracted with 3x
CH2Cl2 and the combined organic extracts were dried over anhydrous MgSO4, filtered and
over cotton wool prior to evaporation into a polypropylene tube, which was stored in a freezer to ensure proper stability.
Primary benzylic fluorides
4-(fluoromethyl)biphenyl,4 1-tert-butyl-4-(fluoromethyl)benzene,41 1-bromo-4-
(fluoromethyl)benzen41 , and 1-(fluoromethyl)-3-methoxybenzene52 were synthesized
according to literature protocols.
1-chloro-4-(fluoromethyl)benzene. Following general procedure A on a
4.86 mmol scale of commercially-available 4-chlorobenzyl bromide, the product (370 mg, 53%) was obtained as a colorless oil by flash chromatography using hexane/ethyl acetate (99/1). 1H NMR (500 MHz, CDCl 3) δ 5.35 (d, J = 47.7 Hz, 2H), 7.31 (d, J = 7.5 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H); 13C NMR (125 MHz, CDCl 3) δ 83.9 (d, J = 166.1 Hz), 128.95 (d, J = 1.8 Hz), 128.98 (d, J = 3.2 Hz), 134.7 (d, J = 10.3 Hz), 134.8 (d, J = 3.7 Hz); 19F NMR (470 MHz, CDCl 3) δ -207.4 (t, J = 47.6 Hz); IR (ATR, ZnSe) ν =
2962, 1600, 1493, 1466, 1410, 1375, 1214, 1089, 982 cm-1; HRMS-APPI calcd for
C7H6ClF [M]*+ 125.0153, found 125.0123.
1-(bromomethyl)-4-methoxybenzene. To a stirred solution of
triphenylphosphine (3.17 g, 12.09 mmol, 1 equiv.) in anhydrous dichloromethane (20 mL) was added bromine (681 μL, 13.30 mmol, 1.1 equiv.) dropwise at 0 °C. The resulting solution was stirred for 30 min at room temperature then cooled to – 78 °C, at which point a solution of commercially-available 4-methoxybenzyl alcohol (1.5 mL, 12.09 mmol, 1 equiv.) in 20 mL anhydrous dichloromethane was added. The reaction mixture was stirred 90 minutes at room temperature. The reaction was quenched with an aqueous solution of Na2S2O3 (0.95 M)and NaHCO3 (1.19 M) and extracted with CH2Cl2
(3x). The combined organic extracts were washed with brine, dried with MgSO4, filtered
and evaporated under reduced pressure. The desired compound (2.48 g, 100%) was
obtained as a colorless oil by trituration using 100% hexanes. Spectral data were identical to those previously reported.53
1-(fluoromethyl)-4-methoxybenzene. Following general procedure A
on a 12.20 mmol scale of 1-(bromomethyl)-4-methoxybenzene, the product (709 mg, 41%) was obtained as a colorless oil by flash chromatography using hexane/ethyl acetate (95/5). This compound was isolated in a polypropylene tube and stored in the freezer due to its unusual instability, which had already been described in previous literature. Spectral data corresponds to what had been published.54
(4-nitrophenyl)methanol. To a stirred solution of commercially-
available 4-nitrobenzaldehyde (1.51 g, 9.93 mmol, 1 equiv.) in 5 mL of absolute EtOH was added a suspension of NaBH4 (274 mg, 6.55 mmol, 0.66 equiv.) in
15 mL of EtOH. The reaction was then stirred for 30 minutes at room temperature. When the reaction is complete, the mixture is quenched with a 10% aq. NaOH solution and stirred until an homogeneous solution is obtained. Ethanol is then evaporated under reduced pressure and the resulting aqueous phase is extracted with CH2Cl2 (3x). The combined
organic extracts are washed with aq. NaHCO3 (2x) then H2O (2x), dried over Na2SO4,
filtered and concentrated to yield the pure title compound (1.39 g, 91%) as a yellowish solid. Spectral data were identical to those previously reported.55
53 Louafi, F.; Hurvois, J.-P.; Chibani, A.; Roisnel, T. J. Org. Chem. 2010, 75, 5721. 54 Makino, K.; Yoshioka, H. J. Fluorine Chem. 1987, 35, 677.
1-(bromomethyl)-4-nitrobenzene. To a stirred solution of
triphenylphosphine (495 mg, 1.80 mmol, 1.1 equiv.) in anhydrous dichloromethane (5 mL) was added bromine (104 μL, 2.04 mmol, 1.25 equiv.) dropwise at 0 °C. The resulting solution was stirred for 30 min at room temperature then cooled to – 78 °C, at which point a solution of (4-nitrophenyl)methanol, 257 mg, 1.63 mmol, 1 equiv.) in 8 mL anhydrous dichloromethane was added. The reaction mixture was stirred 90 minutes at room temperature. The reaction was quenched with an aqueous solution of Na2S2O3 (0.95
M)and NaHCO3 (1.19 M) and extracted with CH2Cl2 (3x). The combined organic extracts
were washed with brine, dried with MgSO4, filtered and evaporated under reduced
pressure. The crude reaction mixture was then purified by silica gel chromatography using hexanes/ethyl acetate (90/10) to isolate the pure title compound (338 mg, 96%) as a yellowish solid. Spectral data were identical to those previously reported.56
1-(fluoromethyl)-4-nitrobenzene. Following general procedure A on a
1.14 mmol scale of 1-(bromomethyl)-4-nitrobenzene, the desired product (103 mg, 58%) was obtained as a slightly orange solid after column chromatography using hexanes/ethyl acetate (90/10). Spectral data were identical to those previously reported.59
4-formylphenyl acetate. To a stirred solution of commercially-available 4-
hydroxybenzaldehyde (1.0 g, 8.18 mmol, 1 equiv.) in 10 mL ethyl acetate at 0 °C, under argon was added triethylamine (1.4 mL, 8.18 mmol, 1 equiv.) followed by acetyl chloride
(582 μL, 8.18 mmol, 1 equiv.) with 5 mL ethyl acetate. The reaction mixture was stirred 5 h at room temperature. The reaction was filtered and evaporated, affording the pure title compound (1.52 g, 100%) as a clear liquid. Spectral data were identical to those previously reported.57
4-(hydroxymethyl)phenyl acetate. In a round-bottomed flask, 4-formylphenyl acetate (SI- 9, 1.5 g, 9.13 mmol, 1 equiv.) was diluted in absolute ethanol (20 mL), then sodium
borohydride (220 mg, 6.03 mmol, 0.66 equiv.) was added at -78 °C. The reaction mixture was allowed to stir for 30 minutes at room temperature, upon which the reaction appeared completed by TLC analysis. The reaction mixture was filtered. Water was added and ethanol was carefully evaporated under reduced pressure. The aqueous mixture was extracted with 3x CH2Cl2 and the combined organic extracts were washed with NaHCO3
(aq. 5%), then water. The solution was dried over anhydrous Na2SO4, filtered and
concentrated in vacuo, affording the pure title compound (683 mg, 45%) as a clear liquid. Spectral data were identical to those previously reported.58
4-(fluoromethyl)phenyl acetate. Using the deoxofluorination general procedure (B), on
4.09 mmol of 4-(hydroxymethyl)phenyl acetate, 1.1 equiv. of Me-DAST and 1.1 equiv. of 4-(trimethylsilyl)morpholine, the title compound (161 mg, 23%) was obtained by column chromatography using hexanes/ethyl acetate (85/15) as a colorless oil. 1H NMR (500 MHz,
CDCl3) δ 2.31 (s, 3H), 5.36 (d, J = 47.8 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 7.3
Hz, 2H); 13C NMR (125 MHz, CDCl
3) δ 21.3, 84.1 (d, J = 165.6 Hz), 121.9 (d, J = 1.3 Hz),
128.9 (d, J = 5.7 Hz), 133.9 (d, J = 17.4 Hz), 151.0 (d, J = 3.3 Hz), 169.5; 19F NMR (470
MHz, CDCl3) δ -206.3 (t, J = 47.7 Hz); IR (ATR, ZnSe) ν = 1757,1610, 1509, 1422, 1370,
1215, 1187, 1165, 1105 cm-1; HRMS-ESI calcd for C
9H9O2 [M-F]+ 149.0603, found
149.0589.
1-chloro-3-(fluoromethyl)benzene. Following general procedure A on a
5.20 mmol scale of commercially-available 3-chlorobenzyl bromide, the product (370 mg, 49%) was obtained as a colorless oil by flash chromatography using
57 Kim, B. R.; Sung, G. H.; Lee, S.-G.; Yoon, Y. J. Tetrahedron 2013, 69, 3234. 58 Lee, J.; Ryu, T.; Park, S.; Lee, P. H. J. Org. Chem. 2012, 77, 4821.
hexane/ethyl acetate (98/2). 1H NMR (500 MHz, CDCl 3) δ 5.35 (d, J = 47.4 Hz, 2H), 7.24- 7.25 (m, 1 H), 7.30-7.33 (m, 2H), δ 7.37 (s, 1H); 13C NMR (125 MHz, CDCl 3) δ 83.7 (d, J = 167.3 Hz), 125.3 (d, J = 6.2 Hz), 127.4 (d, J = 6.5 Hz), 128.9 (d, J = 2.7 Hz), 130.1, 134.7, 138.3 (d, J = 17.1 Hz); 19F NMR (470 MHz, CDCl 3) δ -199.6 (t, J = 47.9 Hz); IR (ATR, ZnSe) ν = 2960, 1602, 1578, 1477, 1433, 1374, 1213, 1165, 1097 cm-1; HRMS-
APPI calcd for C7H6ClF [M*]+ 144.0137, found 144.0114.
1-chloro-2-(fluoromethyl)benzene. Following General Procedure A on a
9.73 mmol scale of commercially-available 2-chlorobenzyl bromide, the product (695 mg, 49%) was obtained as a colorless oil by flash chromatography using hexane/ethyl acetate (99/1). 1H NMR (500 MHz, CDCl
3) δ 5.51 (d, J
= 47.2 Hz, 2H), 7.28-7.33 (m, 2H), 7.39 (d, J = 7.2 Hz, 1H), 7.48 (d, J = 6.3 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 81.8 (d, J = 167.7 Hz), 127.1, 128.6 (d, J = 8.8 Hz), 129.5,
129.9 (d, J = 2.4 Hz), 132.5 (d, J = 5.2 Hz), 134.3 (d, J = 17.7 Hz); 19F NMR (470 MHz,
CDCl3) δ -217.3 (t, J = 47.2 Hz); IR (ATR, ZnSe) ν = 1598, 1577, 1477, 1443, 1379, 1214,
1134, 1058, 1041; HRMS-APPI calcd for C7H6Cl [M-F]*+ 125.0158, found 125.0156.
1-bromo-2-(fluoromethyl)benzene. Following General Procedure A on a 8
mmol scale of commercially-available 2-bromobenzyl bromide, the product (1,05 g, 69%) was obtained as a colorless oil by flash chromatography using hexane/ethyl acetate (98/2). 1H NMR (500 MHz, CDCl 3) δ 5.47 (d, J = 47.2 Hz, 2H), 7.21 (t, J = 7.5 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H); 13C NMR (125 MHz, CDCl 3) δ 83.8 (d, J = 168.2 Hz), 121.7 (d, J = 5.3 Hz), 127.7, 128.6 (d, J = 9.5 Hz), 130.0 (d, J = 2.3 Hz), 132.7, 136.0 (d, J = 17.8 Hz); 19F NMR (470 MHz, CDCl3) δ -216.5 (t, J = 47.1 Hz); IR (ATR, ZnSe) ν = 1595, 1571, 1473, 1442, 1377,
1276, 1207, 1128, 1047 cm-1; HRMS-APPI calcd for C
7H6Br [M-F]*+ 168.9653, found
Secondary benzylic fluorides
1-chloro-4-(1-fluoroethyl)benzene, was synthesised according to a literature protocol.
1-(2,6-dichlorophenyl)ethanol. In a round-bottomed flask, 2,6-dichlorobenzaldehyde (1 g,
5.71 mmol, 1 equiv.) was diluted in 15 mL Et2O. This solution was cooled to 0 °C using an
ice bath, upon which methylmagnesium bromide (3.0M in Et2O, 2.38 mL, 7.14 mmol, 1.25
equiv.) was slowly added. The mixture was stirred for one hour and then quenched with 20 mL of a 5% aqueous H2SO4 solution. The mixture was ectracted with 3x Et2O, the
combined organic extracts were washed with H2O, 2x saturated Na2S2O3, 2x saturated
NaHCO3, then brine. The organic phase was dried over Na2SO4, filtered and evaporated.
Following silica gel chromatography (95/5 hexanes/AcOEt), the title compound (919 mg, 84%) was obtained as a colorless liquid. 1H NMR (400 MHz, CDCl
3) δ 1.64 (d, J = 6.8 Hz,
3H), 2.99 (m, 1H), 5.59 (m, 1H), 7.12 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 21.7, 68.4, 128.8, 129.5, 134.0, 138.8; IR (ATR, ZnSe) ν =
3370, 2976, 1561, 1436, 1103, 1069, 775, 758, 730 cm-1; HRMS-ESI m/z calcd for
C8H7Cl2 [M-OH]+ 172.9925, found 172.9921.
1,3-dichloro-2-(1-fluoroethyl)benzene. Using the deoxofluorination general procedure
(B), on 2.36 mmol of 1-(2,6-dichlorophenyl)ethanol, 2 equiv of Me-DAST and 2.2 equiv of TMS-morpholine, the title compound (359 mg, 79%) was obtained by column chromatography (100% pentane) as a colorless oil. 1H NMR (400 MHz, CDCl
3) δ 1.77 (dd,
J = 22.3, 6.7 Hz, 3H), 6.28 (dq, J = 46.2, 6.7 Hz, 1H), 7.17 (t, J = 7.9 Hz, 1H), 7.31 (d, J =
8.0 Hz, 2H); 13C NMR (100 MHz, CDCl
3) δ 19.4 (dd, J = 19.2, 2.8 Hz), 88.1 (d, J = 137.6
(376 MHz, CDCl3) δ -176.7 (m); IR (ATR, ZnSe) ν = 2982, 1564, 1437, 1196, 1088, 792,
778, 762, 729 cm-1; HRMS-APPI calcd for C
8H7Cl2F [M]*+ 191.9909, found 191.9934.
2-(1-fluoroethyl)naphthalene. Using the deoxofluorination general
procedure (B) on 2.90 mmol of commercially-available α-methyl-2- naphtalenemethanol, 1.05 equiv of Me-DAST and 1.1 equiv of TMS- morpholine, the title compound (200 mg, 40%) was obtained as a white solid after column chromatography (100% hexanes). Spectral data were identical to those previously reported.59
2-(difluoromethyl)naphthalene. Inspired by a literature protocol,Erreur ! Signet non défini.in a round-bottomed flask, Et3N•3HF (1.04 mL, 6,40 mmol, 2 equiv.) was added to 10 mL
CH2Cl2. XtalFluor-E (1.1 g, 4.80 mmol, 1.5 equiv.) was then added, upon which 2-
naphtaldehyde (500 mg, 3.20 mmol, 1 equiv.) was added. The mixture was stirred for 20 hours at room temperature. Aqueous 5% NaHCO3 was then poured in to quench the
reaction and the mixture was stirred for 15 minutes. The organic phase is separated and the aqueous phase was extracted twice with CH2Cl2. The combined organic extracts were dried
over MgSO4, filtered over silica gel and evaporated. Following silica gel chromatography
(98/2 hexanes/AcOEt), the title compound (349 mg, 61%) was obtained as a white solid. Spectral data were identical to those previously reported.60
59 Blessley, G.; Holden, P.; Walker, M.; Brown, J. M.; Gouverneur, V. Org. Lett. 2012, 14, 2754. 60 Prakash, G. K. S.; Ganesh, S. K.; Jones, J.-P.; Kulkarni, A.; Masood, K.; Swabeck, J. K.; Olah, G. A.
Friedel-Crafts reactions
General procedure of Friedel-Crafts reaction of benzylic fluorides (Procedure C):
To a stirred solution of benzylic fluorides (1 equiv.) in CH2Cl2 (90% of the volume
required for substrate concentration of 0.25 M) was added the arene nucleophile (5 equiv.) Finally, 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) (10% of the volume required for substrate concentration of 0.25 M, resulting in a 9:1 mixture of CH2Cl2:HFIP) was added.
The resulting solution was stirred for 18 h at room temperature. The reaction was quenched with H2O and extracted with CH2Cl2 (3x). The combined organic extracts were washed
with brine, dried with MgSO4, filtered and evaporated under reduced pressure. After silica
gel chromatography, pure compounds are usually obtained.
2-(4-(tert-butyl)benzyl)-1,4-dimethylbenzene. Following general
procedure C on a 0.285 mmol scale of the product of the procedure C, the product (65 mg, 90%) was obtained as a colorless oil by flash chromatography using hexane/ethyl acetate (99/1). 1H NMR
(400 MHz, CDCl3) δ 1.29 (s, 9H), 2.20 (s, 3H), 2.28 (s, 3H), 3.91 (s, 2H), 6.94-6.96 (m,
2H), 7.03-7.05 (m, 3H), 7.26-7.28 (m, 2H); 13C NMR (125 MHz, CDCl
3) δ 19.4, 21.3, 31.5,
34.5, 39.0, 125.4, 127.2, 128.4, 130.3, 130.9, 133.6, 135.5, 137.6, 139.0, 148.7; IR (ATR, ZnSe) ν = 2961, 2866, 1614, 1514, 1504, 1460, 1411, 1393, 1375 cm-1; HRMS-APPI calcd
1-tert-butyl-4-(4-methylbenzyl)benzene. Following general
procedure C on a 0.12 mmol scale of the product of the procedure C, the product (28 mg, 90% 3:1 mixture of regioisomers) was obtained as a colorless oil by flash chromatography using hexane/ethyl acetate (99/1). 1H
NMR (400 MHz, CDCl3) δ 1.29 (s, 9H), 2.25 (s, 0.7H, minor), 2.31 (s, 2.1H, major), 3.90
(s, 1.5H, major), 3.95 (s, 0.6H, minor), 7.09-7.15 (m, 5H), 7.28-7.30 (m, 3H); 13C NMR
(125 MHz, CDCl3) δ 19.8, 21.2, 31.5, 34.5, 39.0, 41.1, 125.4 (minor), 125.5 (major), 126.1
(minor), 126.5 (minor), 128.5 (minor), 128.6 (major), 129.0 (major), 129.3 (major), 130.1 (minor), 130.4 (minor), 135.6, 136.7, 137.4, 138.4, 138.5, 139.3, 148.80, 148.84; IR (ATR, ZnSe) ν = 2961, 2904, 1867, 1512, 1462, 1411, 1363, 1268, 1108 cm-1; HRMS-APPI m/z
calcd for C18H22 [M*]+ 238.1716, found 238.1677.
4-(4-tert-butylbenzyl)-1,2-dimethylbenzene. Following general
procedure C on a 0.3 mmol scale of the product of the procedure C, the product (67 mg, 89% 4.3:1 mixture of regioisomers) was obtained as a white solid by flash chromatography using hexane/ethyl acetate (98/2). 1H
NMR (400 MHz, CDCl3) δ 1.29 (s, 9H), 2.14 (s, 0.5H), 2.21 (s, 4.8H), 2.28 (s, 0.6H), 3.87 (s, 1.5H, major), 3.97 (s, 0.4H, minor), 6.93-6.94 (m, 0.8H), 6.98 (s, 1H), 7.03-7.05 (m, 1.7H), 7.10-7.12 (m, 1.6H), 7.27-7.29 (m, 2H); 13C NMR (125 MHz, CDCl 3) δ 15.6, 19.5, 20.0, 20.9, 31.5, 34.5, 39.6, 41.2, 125.4, 125.5, 125.5, 126.4, 128.2, 128.3, 128.4, 128.5, 129.8, 130.4, 134.3, 136.7, 138.6, 138.8, 148.8; IR (ATR, ZnSe) ν = 2962, 2867, 1615, 1513, 1505, 1457, 1411, 1392, 1383 cm-1; HRMS-APPI calcd for C
19H24 [M*]+ 252.1878,
found 252.1854.
1-benzyl-4-tert-butylbenzene. 1-tert-butyl-4- (fluoromethyl)benzene (50 mg, 0.3 mmol, 1 equiv) was dissolved in benzene (1.08 mL, 90% of the volume required for a 0.25 M substrate concentration). HFIP (120 μL, 10% of the volume required for a 0.25 M substrate concentration, resulting in a 9:1 PhH:HFIP mixture) was then added and the resulting solution was allowed to stir for 18 h at room temperature. The reaction was quenched with H2O and extracted with CH2Cl2 (3x). The combined organic extracts were washed with
brine, dried with MgSO4, filtered and evaporated under reduced pressure. After silica gel
chromatography using 100% hexanes, the title compound (37 mg, 57%) was isolated as a colorless liquid. 1H NMR (400 MHz, CDCl
3) δ 1.30 (s, 9H), 3,95 (s, 2H), 7.12, (d, J = 8.1
Hz, 2H), 7.17-7.21 (m, 3H), 7.25-7.31 (m, 4H); 13C NMR (100 MHz, CDCl
3) δ 31.5, 34.5,
41.6, 125.5, 126.1, 128.56, 128.63, 129.1, 138.2, 141.4, 149.0; IR (ATR, ZnSe) ν = 2962, 2903, 1514, 1494, 746, 729, 697 cm -1; HRMS-APPI m/z calcd for C
17H20 [M*]+ 224.1560,
found 2245.1551.
2-(4-(tert-butyl)benzyl)naphthalene. Following General Procedure C on a 0.3 mmol scale of the product of the procedure C, and using 10 equiv. of naphthalene as nucleophile, the product (66 mg, 80%, 2.8:1 mixture of regioisomers) was obtained as a white solid by flash chromatography using 100% hexanes. 1H NMR (500 MHz, CDCl
3) δ 1.28 (s, 6.3H), 1.29 (s, 2.6H), 4.11 (s, 0.5H), 4.42 (s, 1.4H), 7.11-7.16 (m, 2.1H), 7.25-7.31 (m, 3H), 7.40-7.46 (m, 3H), 7.64 (s, 0.3H), 7.74-7.78 (m, 1.6H), 7.84-7.86 (m, 0.8H), 8.01- 8.03 (m, 0.7H); 13C NMR (125 MHz, CDCl 3) δ 14.3, 22.8, 31.53, 31.54, 34.48, 34.51, 38.6, 41.7, 124.5, 125.4, 125.46, 125.52, 125.65, 125.70, 126.0, 126.1, 127.18, 127.21, 127.4, 127.7, 127.8, 127.9, 128.0, 128.2, 128.5, 128.7, 128.8, 132.2, 132.3, 133.8, 134.1, 137.0, 137.7, 138.1, 138.9, 148.9, 149.0; IR (ATR, ZnSe) ν = 3023, 2958, 2901, 2864, 1908, 1688, 1511 cm-1; HRMS-APPI m/z calcd for C
21H22 [M*]+ 274.1722, found 274.1679.
1-(4-(tert-butyl)benzyl)-2-methoxybenzene. Following General Procedure C on a 0.3 mmol scale of the product of the procedure C, the product (67 mg, 88%, 1.4:1 mixture of regioisomers) was obtained as a white solid by flash chromatography using hexane/ethyl acetate (99/1). 1H NMR (400 MHz, CDCl
3) δ 1.29 (s, 9H), 3.78 (s, 1.7H, major), 3.82 (s,
1.2H, minor), 3.89 (s, 1H, major), 3.94 (s, 0.9H, minor), 6.81-6.88 (m, 2H), 7.06-7.18 (m, 4H), 7.27-7.30 (m, 2H); 13C NMR (100 MHz, CDCl
3) 31.5, 31.6, 34.47, 34.49, 35.3, 40.6,
55.4, 55.5, 110.5, 114.0, 120.6, 125.3, 125.5, 127.4, 128.5, 128.7, 130.0, 130.4, 133.5, 138.0, 138.7, 148.6, 148.9, 157.4. 158.0; IR (ATR, ZnSe) ν =3014, 2955, 1492, 1246, 1029, 755, 666 cm-1; HRMS-APPI m/z calcd for C
2-(4-(tert-butyl)benzyl)thiophene. Following General Procedure C
on a 0.3 mmol scale of the product of the procedure C, and using 10 equiv. of thiophene as nucleophile, the product (62 mg, 90%, 3:1 mixture of regioisomers) was obtained as a colorless oil by flash chromatography using hexane/ethyl acetate (98/2). 1H NMR (500 MHz, CDCl 3) δ 1.30 (s, 9H), 3.95 (s, 0.5H, minor), 4.12 (s, 1.5H, major), 6.80-6.81 (m, 0.7H), 6.91-6.92 (m, 1.3H), 7.12-7.14 (m, 1.4H), 7.16-7.18 (m, 1.6H), 7.30-7.33 (m, 2.3H), 7.47-7.48 (m, 0.7H), 7.83-7.85 (m, 0.8H); 13C NMR (125 MHz, CDCl 3) δ 31.52, 31.54, 34.6, 35.6, 36.1, 121.3, 124.0, 125.2, 125.5, 125.6, 125.7, 126.9, 128.3, 128.5, 128.7, 137.5, 137.7, 144.4, 149.1, 149.4; IR (ATR, ZnSe) ν = 2961, 2903, 2867, 1514, 1464, 1433, 1411 cm-1; HRMS-APPI m/z calcd for C
15H18S
[M*]+ 230.1129, found 230.1081.
2-(4-(tert-butyl)benzyl)-1-methyl-1H-pyrrole. To a stirred solution of the product of the procedure C, (50 mg, 0.3 mmol, 1 equiv.) in 1,2-dichloroethane (1.08 mL, 90% of the volume required for substrate concentration of 0.25 M) was added the N- methylpyrrole (266 μL, 3.0 mmol, 10 equiv.) Finally, 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) (120 μL, 10% of the volume required for substrate concentration of 0.25 M, resulting in a 9:1 mixture of DCE:HFIP) was added. The resulting solution was stirred for 18 h at 60 °C. After a work-up as described in General Procedure C, the product (54 mg, 80%, 1.3:1 mixture of regioisomers) was purified to a colorless oil by flash chromatography using hexanes/ethyl acetate (90/10). 1H NMR (400 MHz, CDCl
3) δ 1.29
(s, 9H), 3.42 (s, 1.2H, minor), 3.56 (s, 1.8H, major), 3.77(s, 1.2H, major), 3.89 (s, 0.9H, minor), 5.90 (m, 0.3H), 5.97 (m, 0.5H), 6.05-6.06 (m, 0.4H), 6.34 (m, 0.5H), 6.49 (m, 0.5H), 6.55 (m, 0.4H), 7.06-7.08 (m, 0.9H), 7.16-7.18 (m, 1.4H), 7.28-7.30 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 31.5, 31.6, 32.4, 33.1, 34.0, 34.46, 34.50, 36.2, 106.7, 107.9,
108.8, 120.0, 121.77, 121.82, 123.7, 125.3, 125.5, 128.2, 128.3, 131.8, 136.5, 139.5, 148.5, 149.1; IR (ATR, ZnSe) ν = 2959, 2902, 1513, 1505, 1464, 1415, 1393; HRMS-APPI m/z calcd for C16H22N [M+H]+ 228.1747, found 228.1750.
1-tert-butyl-4-(4-fluorobenzyl)benzene. 1-tert-butyl-4- (fluoromethyl)benzene (33 mg, 0.2 mmol, 1 equiv) was dissolved in fluorobenzene (0.72 mL, 90% of the volume required for a 0.25 M substrate concentration). HFIP (80 μL, 10% of the volume required for a 0.25 M substrate concentration, resulting in a 9:1 PhF:HFIP mixture) was then added and the resulting solution was allowed to stir for 18 h at room temperature. A work-up as described in General Procedure C was then performed. After silica gel chromatography using 100% hexanes, the title compound (27 mg, 56%, 32:4:1 mixture of para:ortho:meta regioisomers) was isolated as a colorless liquid. 1H NMR (400 MHz, CDCl
3) δ 1.31 (m, 9H), 3.86 (s, 0.1H), 3.93 (s, 1.7H, major), 3.98 (s, 0.2H), 6.97 (m, 1.6H), 7.05 (m, 0.2H), 7.11 (m, 1.5H), 7.16 (m, 2H), 7.32 (m, 1.8H), 19F NMR (470 MHz, CDCl 3) δ -117.6 (tt, J = 8.9, 5.3 Hz, 1F, major), -117.8 (ddd, J = 14.2, 8.9, 5.5 Hz, 0.12F), -117.9 (m, 0.07F); 13C NMR (126 MHz, CDCl3) δ 31.5, 34.5, 40.7, 115.3 (d, J = 21.0 Hz), 125.6, 128.6, 130.4 (d,
J = 7.6 Hz), 137.1 (d, J = 2.9 Hz), 138.0, 149.1, 161.5 (d, J = 243.7 Hz) (para isomer only);
IR (ATR, ZnSe) ν = 3024, 2962, 1507, 1223, 1156, 814, 733 cm-1; HRMS-APPI m/z calcd
for C17H19F [M*]+ 242.1465, found 242,1445.
4-(2,5-dimethylbenzyl)biphenyl. Following General Procedure C
on a 0.120 mmol scale of 4-(fluoromethyl)biphenyl, the product (30 mg, 99%) was obtained in pure form as a colorless oil directly after work-up. Spectral data were identical to those previously reported.61
2-(4-chlorobenzyl)-1,4-dimethylbenzene. To a stirred solution of 1-chloro-4-(fluoromethyl)benzene (40 mg, 0.27 mmol, 1 equiv.)
in 1,2-dichloroethane (1.08 mL, 90% of the volume required for substrate concentration of 0.25 M) was added p-xylene (166 μL, 1.5 mmol, 5 equiv.) Finally, HFIP (120 μL, 10% of the volume required for substrate concentration of 0.25 M, resulting in a 9:1 mixture of DCE:HFIP) was added. The resulting solution was stirred for 18 h at 60 °C in a sealed vessel. After a work-up as described in General Procedure C, the product (40 mg, 64%) was obtained as a colorless oil by silica gel chromatography using 100% hexanes. 1H NMR
(500 MHz, CDCl3) δ 2.16 (s, 3H), 2.28 (s, 3H), 3.90 (s, 2H), 6.89 (s, 1H), 6.97 (d, J = 7.6
Hz, 1H), 7.03-7.05 (m, 3H), 7.22 (d, J = 8.3 Hz, 2H); 13C NMR (125 MHz, CDCl
3) δ 19.3,
21.1, 38.9, 127.4, 128.6, 130.1, 130.4, 130.8, 131.7, 133.5, 135.6, 138.3, 139.2; IR (ATR, ZnSe) ν = 2920, 1615, 1489, 1441, 1406, 1378, 1155 cm-1; HRMS-APPI calcd for.C
15H15Cl
[M*]+ 230.0857, found 230.0852.
2-(4-bromobenzyl)-1,4-dimethylbenzene. To a stirred solution of 1-bromo-4-(fluoromethyl)benzene (50 mg, 0.266 mmol, 1 equiv.)
in dichloromethane (532 μL, 50% of the volume required for substrate concentration of 0.25 M) was added p-xylene (164 μL, 1.33 mmol, 5 equiv.) Finally, HFIP (532 μL, 50% of the volume required for substrate concentration of 0.25 M, resulting in a 1:1 mixture of CH2Cl2:HFIP) was added. The resulting solution was stirred
for 18 h at room temperature. After a work-up as described in General Procedure C, the product (44 mg, 60%) was obtained as a colorless oil by flash chromatography using 100% hexanes. 1H NMR (500 MHz, CDCl
3) δ 2.16 (s, 3H), 2.28 (s, 3H), 3.87 (s, 2H), 6.81 (s,
1H), 6.97-6.98 (m, 3H), 7.04 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 8.3 Hz, 2H); 13C NMR (125
MHz, CDCl3) δ 19.3, 21.1, 39.0, 119.8, 127.5, 130.4, 130.6 130.8, 131.5, 133.5, 135.6,
138.1, 139.7; IR (ATR, ZnSe) ν = 2919, 1503, 1485, 1444, 1401, 1378, 1188 cm-1; HRMS-
APPI calcd for C15H15Br [M*]+ 274.0352, found 274.0311.
2-(4-methoxybenzyl)-1,4-dimethylbenzene. Following General
Procedure C on a 0.35 mmol scale of 1-(fluoromethyl)-4- methoxybenzene, no desired compound could be obtained and a polymeric solid compound was isolated as the only product of the
reaction. The extremely high reactivity of 1-(fluoromethyl)-4-methoxybenzene hinders any attempt at controlling its Friedel-Crafts reaction. Other conditions tested were CH2Cl2 :
HFIP (9:1), -78 °C, 18 h and CH2Cl2 : HFIP (19:1), r.t., 18 h. None of these yielded the
desired compound and only the polymer was obtained.
4-(2,5-dimethylbenzyl)phenyl acetate. To a stirred solution of 4- (fluoromethyl)phenyl acetate (20 mg, 0.12 mmol, 1 equiv.) in
dichloromethane (47 μL mL, 10% of the volume required for substrate concentration of 0.25 M) was added p-xylene (73 μL, 0.59 mmol, 5 equiv.) Finally, HFIP (420 μL, 90% of the volume required for substrate concentration of 0.25 M, resulting in a 1:9 mixture of CH2Cl2:HFIP) was added. The
resulting solution was stirred for 18 h at room temperature. After a work-up as described in General Procedure C, the product (23.4 mg, 77%) was obtained as a colorless oil by flash chromatography using hexane/ethyl acetate (90/10). 1H NMR (500 MHz, CDCl
3) δ 2.18 (s,
3H), 2.28 (s, 3H), 2.29 (s, 3H), 3.93 (s, 2H), 6.92 (s, 1H), 6.96-6.98 (m, 3H), 7.04 (d, J = 7.5 Hz, 1H), 7.10 (d, J = 8.3 Hz, 2H); 13C NMR (125 MHz, CDCl
3) δ 19.3, 21.1, 21.3, 38.9,
121.5, 127.3, 129.7, 130.4, 130.9, 133.5, 135.6, 138.2, 138.5, 148.9, 169.8; IR (ATR, ZnSe) ν = 2921, 1759, 1504, 1440, 1404, 1367, 1187 cm-1; HRMS-ESI m/z calcd for C
17H19O2
[M+H]+ 255.1380, found 255.1384.
2-(3-methoxybenzyl)-1,4-dimethylbenzene. To a stirred solution
of 1-(fluoromethyl)-3-methoxybenzene (50 mg, 0.35 mmol, 1 equiv.) in dichloromethane (0.7 mL, 50% of the volume required for substrate concentration of 0.25 M) was added p-xylene (432 μL, 3.5 mmol, 10 equiv.) Finally, HFIP (0.7 mL, 50% of the volume required for substrate concentration of 0.25 M, resulting in a 1:1 mixture of CH2Cl2:HFIP) was added. The
resulting solution was stirred for 18h at room temperature. After a work-up as described in General Procedure C, the product (39 mg, 50%) was obtained as a colorless oil by flash chromatography using 100% hexanes. 1H NMR (400 MHz, CDCl
3) δ 2.19 (s, 3H), 2.27 (s,
3H), 3.75 (s, 3H), 3.92 (s, 2H), 6.67 (s, 1H), 6.70-6.73 (m, 2H), 6.92-6.96 (m, 2H), 7.04 (d,
J = 7.5 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H); 13C NMR (125 MHz, CDCl
55.2, 111.0, 114.8, 121.3, 127.2, 129.4, 130.3, 130.8, 133.6, 135.5, 138.6, 142.4, 159.8; IR (ATR, ZnSe) ν = 2920, 1615, 1592, 1570, 1502, 1470, 1442 cm-1; HRMS-APPI m/z calcd
for C16H18O [M*]+ 226.1353, found 226.1320.
2-(3-chlorobenzyl)-1,4-dimethylbenzene. To a stirred solution of 1- chloro-3-(fluoromethyl)benzene (47 mg, 0.325 mmol, 1 equiv.) in
1,2-dichloroethane (650 μL, 50% of the volume required for substrate concentration of 0.25 M) was added p-xylene (200 μL, 1.63 mmol, 5 equiv.) Finally, HFIP (650 μL, 50% of the volume required for substrate concentration of 0.25 M, resulting in a 1:1 mixture of DCE:HFIP) was added. The resulting solution was stirred for 18h at 60 °C. After a work-up as described in General Procedure C, the title compound (50 mg, 66%) was obtained as a colorless oil by flash chromatography using hexane/ethyl acetate (99/1). 1H NMR (500 MHz, CDCl
3) δ 2.18 (s, 3H), 2.30 (s, 3H),
3.92 (s, 2H), 6.91 (s, 1H), 6.98 (t, J = 7.6 Hz, 2H), 7.05 (d, J = 7.6 Hz, 1H), 7.09 (s, 1H), 7.16-7.18 (m, 2H); 13C NMR (125 MHz, CDCl
3) δ 19.3, 21.1, 39.2, 126.2, 127.0, 127.5,
128.8, 129.7, 130.5, 130.9, 133.5, 134.3, 135.7, 137.9, 142.8; IR (ATR, ZnSe) ν = 2919, 1595, 1571, 1503, 1473, 1429, 1378; HRMS-APPI m/z calcd for C15H15Cl [M*]+ 230.0857,
found 230.0842.
2-(2-chlorobenzyl)-1,4-dimethylbenzene. To a stirred solution of 1- chloro-2-(fluoromethyl)benzene (51 mg, 0.35 mmol, 1 equiv.) in
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) (1.36 mL, c = 0.25 M) was added p-xylene (210 μL, 1.7 mmol, 5 equiv.). The resulting solution was stirred for 18h at room temperature. Following a work-up as described in General Procedure C, the product (66 mg, 84%) was obtained as a colorless oil by flash chromatography using hexane/ethyl acetate (99/1). 1H NMR (500 MHz, CDCl
3) δ 2.18 (s,
3H), 2.27 (s, 3H), 4.01 (s, 2H), 6.82 (s, 1H), 6.86 (d, J = 6.9 Hz, 1H), 6.9 (d, J = 7.8 Hz, 1H), 7.06-7.15 (m, 3H), 7.37 (d, J = 7.1 Hz, 1H); 13C NMR (125 MHz, CDCl
3) δ 19.2,
21.1, 39.8, 126.9, 127.4, 127.5, 129.4, 130.28, 130.29, 130.7, 133.7, 134.4, 135.6, 137.3, 138.3; IR (ATR, ZnSe) ν = 2920, 1615, 1592, 1570, 1502, 1469, 1442 cm-1; HRMS-APPI
2-(2-bromobenzyl)-1,4-dimethylbenzene. To a stirred solution of 1- bromo-2-(fluoromethyl)benzene (50 mg, 0.26 mmol, 1 equiv.) in 1,2-
dichloroethane (520 μL, 50% of the volume required for substrate