7 Experimental Section
7.6 Experimental details for Chapter 6
Typical procedure for the arylation of ketones with haloindoles.
A vial containing a stirring bar was charged with (Pd(DtBPF)Cl2) 43 (2.0 mol%, 2.6 mg).
haloindole (0.2 mmol, 1.0 equivalents) was added. The vial was then closed with a septum cap and the liquid ketone (0.8 mmol, 4.0 equivalents) was added. The vial was purged three times with Ar/vacuum cycles. A stock solution of NaOH in water was prepared (160 mg/mL, 4.0 M). Under an Ar atmosphere, dioxane (0.2 mL), the ketone and and the aqueous NaOH solution (4.0 equivalents, 0.2 mL) were added through the septum using a syringe. Finally, the vial was stirred at 60°C for 16 h. The solution was cooled to room temperature, then 0.5 mL water and 0.5 mL of ethyl acetate were added and mixed. The aqueous phase was then extracted with ethyl acetate (4 x 1 mL) and the organic phase was filtered through a short pad of MgSO4. The product was then
purified via column chromatography (typically hexane : acetate = 9 : 1). Typical procedure for the arylation of ketones with other haloarenes.
A vial containing a stirring bar was charged with (Pd(DtBPF)Cl2) 43 (2.0 mol%, 2.6 mg).
All the solid coupling partners were added at this stage: solid haloarenes (0.2 mmol, 1.0 equivalents) and/or solid ketones (0.4 mmol, 2.0 equivalents). The vial was then closed with a septum cap and purged three times with Ar/vacuum cycles. A stock solution of NaOH in water was prepared (100 mg/mL ). Under an Ar atmosphere, dioxane (0.2 mL), the liquid ketone and/or the liquid haloarene, and the aqueous NaOH solution (2.5 equivalents, 0.2 mL) were added through the septum using a syringe. Finally, the vial was stirred at 60°C for 16 h. The solution was cooled to room temperature, then 0.5 mL water and 0.5 mL of ethyl acetate were added and mixed. The aqueous phase was then extracted with ethyl acetate (4 x 1 mL) and the organic phase was filtered through a short pad of MgSO4. The product was then purified via
Ph N Ph
H3N Cl-
Synthesis of Prochlorperazine derivative 75.
Proclorperazine dimaleate (0.2 mmol, 121.2 mg) was suspended in 2 mL of ethyl acetate. To this suspension, 2 mL of 1.0 M aqueous Na2CO3 was added. After the
organic phase became clear, the aqueous phase was separated and extracted again with ethyl acetate (4 x 2 mL). The combined organic extract was evaporated and the remaining oil was dissolved in dioxane and transferred to a vial. After evaporation of the solvent, (Pd(DTBPF)Cl2) (5 mol%, 6.5 mg) was weighted in the vial. The vial was
then closed with a septum cap and purged three times with Ar/vacuum cycles. A stock solution of NaOH in water was prepared (160 mg/mL ). Under an Ar atmosphere, dioxane (0.2 mL), propiophenone (2.0 equivalents, 50 uL), and the aqueous NaOH solution (4.0 equivalents, 0.2 mL) were added through the septum using a syringe. Finally, the vial was stirred at 60°C during 16 h. The solution was cooled to r.t., then 0.5 mL water and 0.5 mL of ethyl acetate were added and mixed. The aqueous phase was then extracted with ethyl acetate (4 x 1 mL) and the organic phase was filtered through a short pad of MgSO4 and evaporated. The resultant crude oil was suspended in ethyl
ether (5 mL) and 0.1 M HCl (5 mL). The aqueous phase wash washed with ethyl ether (3 x 5 mL) and then the pH was adjusted to ca. 11 using a saturated solution of Na2CO3.
This basic aqueous solution was then extracted with ethyl acetate (6 x 5mL), dried over MgSO4 and evaporated. The mixture was then purified by flash chromatography (97:3
DCM/MeOH) over pre-treated, basified silica (2% triethylamine in DCM, overnight), affording 248 mg (86%) of the product 75 as a pale, yellow oil.
Synthesis of N-Boc protected halotryptophans 78, 81, 83.23
A suspension of S-7-Br-tryptophan (100 mg, 0.35 mmol, 1.0 eq) and di-t-butyl dicarbonate (92 mg, 0.42 mmol, 1.2 eq) in 1,4-dioxane-water (1:1, 3.0 mL) was cooled to 0 °C. Aqueous KOH (1 M, 0.45 mL, 0.45 mmol, 1.25 eq) was added dropwise. The mixture was stirred overnight while warming to room temperature. The reaction was diluted with water (10 mL) and extracted with diethyl ether (2 x 10 mL). The aqueous layer was cooled in an ice-bath and the pH was adjusted to 2 using 1 M HCl. The resulting white suspension was extracted using ethyl acetate (5 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4 and the solvent was
removed in vacuo to give S-N-Boc-7-Br-tryptophan 83 (120 mg, 89%) as a white, waxy solid that was used without further purification. Analogous procedures were used for the preparation of S-N-Boc-5-Br-tryptophan and 6-Cl-S-tryptophan.
Coupling of N-Boc protected halotryptophans.
S-N-Boc-5-Br-tryptophan (0.05 mmol, 19.2 mg) and [Pd(DtBPF)Cl2] 43 (10 mol%, 3.6
mg) were weighted in a screw-cap vial equipped with a stirring bar. The vial was then purged with 3 cycles of vacuum/Ar. Dioxane (0.1 mL; previously filtered on basic alumina), propiophenone (5.0 equivalents, 30 µL) and an aqueous solution of NaOH
(0.1 mL of a 2M solution, 4.0 equivalents) were added in this order, and the reaction was stirred at 60°C for 16 h. After this time, the reaction was cooled to r.t., 2 mL of water was added and the dioxane was evaporated at the rotavapor. The resulting aqueous solution was extracted with ethyl ether (3 x 3 mL). The pH of the solution was then adjusted to ca. 2, and the resulting suspension was extracted with ethyl acetate (6 x 3 mL). The ethyl acetate phases were combined and dried on Na2SO4, then filtered
and concentrated under vacuum. The crude mixture was then purified either by column chromatography (DCM/Ethyl acetate/formic acid = 9:1:0.1) or by automated column chromatography on C18-functionalised reverse phase silica using a gradient of water and methanol (5-95%) to afford product 79 as a white solid. The same protocol was applied for the synthesis of compounds 81 and 83.
Assessment of the enantiopurity of 83. Boc-deprotection of 83 using TFA
6h (10 mg, 0.023 mmol) was dissolved in CH2Cl2 (1 mL) and transferred to a
microwave vial. TFA (50 µL, ca. 2 mmol) was added and reaction vial was sealed with an aluminium crimp cap. Reaction mixture was heated in a microwave reactor at 60°C for 40 min. After cooling, solvent was evaporated under reduced pressure.
Enantiopurity analysis of tryptophan derivatives by UPLC after derivatisation with Marfey’s reagent.24
The enantiopurity of Boc-deprotected 83 was analysed using Marfey’s Reagent (1- fluoro-2,4-dinitrophenyl-5-L-alanine amide, FDAA).
A stock solution of 10.0 mM FDAA in acetone was prepared by dissolving 2.7 mg FDAA in 1 ml acetone. The sample was dissolved in 1 M sodium hydrogen carbonate (0.5 mg/mL). FDAA (50 µl) stock solution were added to 100 µl of sample solution, and the mixture incubated at 40 °C for 1h. The reaction was quenched with 100 µl of 1 M hydrochloric acid. The reaction mixture was diluted (10 ml in 190 ml water) and centrifuged (13,000 rpm, 5 min). Clear supernatant was analysed by UPLC: the analysis was performed on Waters Acquity UPLC BEH C18 (1.7um 2.1 x 50 mm) column eluting with 0.1% TFA in water (solvent A) and acetonitrile (solvent B). Following gradient was used: 0-0.2 min (20% B), 0.2-4.0 min (20% to 70% B), 4.0-4.2 (70% to 90% B), 4.2-5.2 min (90% B), 5.2-5.5 (90% to 20%B), 5.5-6.0 (20% B). The flow rate was set to 600 µl min-1 and the column temperature was maintained at 50°C. Detection was by
UV (PDA 200-400nm, UV 340 nm). A mixture of S-tryptophan to D-tryptophan was used as a standard to confirm the separation of enantimers. The FDAA derivative of Boc-deprotected 6h revealed only peak, indicating presence of single enantiomer. The stereocenter in the α-position of the ketone carbonyl moiety did not affect the analysis.
Characterisation data. 78. S-N-Boc-5-Br-tryptophan:25 Yield 87%, 123 mg. 1H NMR (400MHz, CD3OD) : δ 7.71 (d, J = 1.6 Hz, 1H), 7.25 (d, J = 8.6 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 7.12 (s, 1H), 4.40 (dd, J = 7.4, 5.0 Hz, 1H), 3.27 (dd, J = 14.6, 4.8 Hz, 1H), 3.09 (dd, J = 14.6, 7.7 Hz, 1H), 1.39 (s, 9H). 13C NMR (101 MHz, CD3OD): δ 175.5, 157.7, 136.6, 130.8, 126.0, 125.0, 122.0, 113.9, 113.0, 111.1, 80.6, 56.0, 29.4, 28.7. [α] 20D = -1.4 (c= 0.5, MeOH)
Analytical data matches previously reported characterisation. 80. S-N-Boc-6-Cl-tryptophan:
Yield 88%, 119 mg,.
1H NMR (400MHz, CD3OD) : δ 7.52 (d, J = 8.5 Hz, 1H), 7.33 (s, 1H), 7.10 (s, 1H), 6.98
(dd, J = 8.4, 1.6 Hz, 1H), 4.39 (dd, J = 7.7, 5.2 Hz, 1H), 3.31-3.24 (m, 1H, partly covered by the solvent signal), 3.09 (dd, J = 14.6, 7.9 Hz, 1H), 1.38 (s, 9H).
13C NMR (101 MHz, CD3OD) : δ 175.7, 157.8, 138.3, 128.2, 127.6, 125.4, 120.5, 120.2,
112.0, 111.6, 80.5, 55.8, 28.7, 28.6. [α] 20D = +5.4 (c= 0.5, MeOH)
HRMS (EI+): m/z calcd for C16H2035ClN2O4: 339.1111, found [M+H]+: 339.1113
82. S-N-Boc-7-Br-tryptophan:26 Yield 91%, 127 mg. 1H NMR (300MHz, CD3OD) : δ 10.55 (bs, 1H), 7.56 (dd, J = 7.9, 0.7 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 7.17 (s, 1H), 6.94 (d, J = 7.7 Hz, 1H), 4.43 (dd, J = 7.7, 5.2 Hz, 1H), 3.31 (dd, J = 14.9, 4.5 Hz, 2H), 3.11 (dd, J = 14.6, 7.8 Hz, 1H), 1.37 (s, 9H). 13C NMR (101 MHz, CD3OD): δ 174.3, 156.3, 129.1, 124.3, 124.2, 123.5, 119.6, 117.5, 111.2, 111.2, 104.1, 79.2, 54.4, 27.4, 27.3. [α] 20D = +15.2 (c= 0.5, MeOH) N H COOH NHBoc Br N H COOH NHBoc Cl N H COOH NHBoc Br
57. 2-(1H-Indol-5-yl)-1-phenylpropan-1-one:
Yield 84%, 126 mg. X=Br, brown solid.
1H NMR (400MHz, CDCl3) : δ 8.19 (bs, 1H), 8.04-7.99 (m, 2H), 7.56 (d, J=1.2 Hz, 1H),
7.46-7.40 (m, 1H), 7.38-7.29 (m, 3H), 7.17-7.14 (m, 1H), 7.13 (dd, J = 8.4, 1.7 Hz, 1H), 6.49 (ddd, J = 3.0, 2.0, 0.9 Hz, 1H), 4.79 (q, J = 6.8 Hz, 1H), 1.59 (d, J = 6.8 Hz, 3H).
13C NMR (101 MHz, CDCl3) : δ 201.0, 136.7, 134.8, 132.9, 132.5, 128.9, 128.3, 124.7, 121.9,
119.7, 111.6, 102.47, 48.0, 20.0. One aromatic carbon was not detected. HRMS (EI+): m/z calcd for C17H17NO: 250.1226, found [M+H]+: 250.1224.
58. 2-(1H-Indol-6-yl)-1-phenylpropan-1-one:
Yield 82%, 123 mg. X=Br, brown solid.
1H NMR (400 MHz, CDCl3) : δ 8.24 (bs, 1H), 8.00 (dt, J = 8.5, 1.7 Hz, 2H), 7.59 (d, J = 8.1 Hz, 1H), 7.48-7.40 (m, 1H), 7.35 (ddt, J = 8.2, 6.8, 1.2 Hz, 2H), 7.27 (s, 1H), 7.13 (m, 1H), 7.10 (dd, J = 8.2, 1.5 Hz, 1H), 6.49 (ddd, J = 3.0, 2.0, 0.9 Hz, 2H), 4.79 (q, J = 6.8 Hz, 1H), 1.59 (d, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) : δ 200.8, 136.6, 136.2, 135.4, 132.6, 128.8, 128.4, 126.7, 124.4, 121.2, 120.3, 109.8, 102.4, 77.0, 48.1, 19.9.
HRMS (EI+): m/z calcd for C17H17NO: 250.1226, found [M+H]+: 250.1226.
59. 2-(1H-Indol-6-yl)-1-phenylpropan-1-one:
Yield 90%, 135 mg. X=Br, brown solid. Yield 85%, 128 mg. X=I. Yield 81%, 122 mg. X=Cl (Pd 5 mol%). 1H NMR (400MHz, CDCl3) : δ 9.13 (s, 1H), 8.10 (d, J = 7.5 Hz, 2H), 7.58 (d, J = 7.9 Hz, 1H), 7.49 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.23 (dd, J = 5.0, 1.9 Hz, 2H), 7.14 (t, J = 7.5 Hz, 1H), 6.54 (ddd, J = 3.0, 2.0, 0.9 Hz, 1H), 5.04 (q, J = 7.0 Hz, 1H), 1.72 (d, J = 7.0 Hz, 7H). 13C NMR (101 MHz, CDCl3) : δ 201.8, 136.3, 133.9, 133.3, 129.1, 128.9, 128.5, 124.7, 122.9, 122.5, 120.2, 120.1, 102.3, 47.2, 16.8.
HRMS (EI+): m/z calcd for C17H17NO: 250.1226, found [M+H]+: 250.1224. O H N O N H O HN
60. 2-(1H-Indol-7-yl)-1-(o-tolyl)-ethan-1-one:
Yield 69%, 103 mg. X=Br, brown solid.
1H NMR (400 MHz, CDCl3): δ 9.21 (s, 1H), 8.00 – 7.87 (m, 1H), 7.56 (dd, J = 6.6, 2.1 Hz,
1H), 7.35 (td, J = 7.5, 1.2 Hz, 1H), 7.29 – 7.23 (m, 2H), 7.20 (d, J = 7.6 Hz, 1H), 7.12 – 6.97 (m, 2H), 6.59 – 6.51 (m, 1H), 4.43 (s, 2H), 2.40 (s, 3H).
13C NMR (101 MHz, CDCl3): δ 201.9, 139.2, 136.9, 135.6, 132.1, 131.8, 129.5, 128.4, 125.64,
124.8, 123.3, 120.0, 117.0, 102.6, 46.7, 21.4. One aromatic carbon was not detected. HRMS (EI+): m/z calcd for C17H17NO: 250.1226, found [M+H]+: 250.1225.
60’. 2,2-di(1H-Indol-7-yl)-1-(o-tolyl)-ethan-1-one:
20 mg, 9% yield of this product were isolated from the reaction for 60, brown solid.
1H NMR (400 MHz, CDCl3): δ 8.28 (s, 2H), 7.89 (d, J = 7.4 Hz, 1H), 7.63 (d, J = 7.8 Hz, 2H), 7.40 (td, J = 7.5, 1.2 Hz, 1H), 7.32 – 7.23 (m, 2H), 7.20 (d, J = 7.2 Hz, 2H), 7.12 (t, J = 7.6 Hz, 2H), 7.01 (t, J = 2.8 Hz, 2H), 6.48 (dd, J = 3.1, 2.1 Hz, 2H), 6.42 (s, 1H), 2.32 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 202.2, 139.1, 138.3, 134.8, 132.1, 131.9, 129.1, 128.7, 125.87, 124.8, 122.5, 120.8, 120.3, 120.0, 102.4, 58.4, 21.0.
HRMS (EI+): m/z calcd for C25H21N2O: 365.1648, found [M+H]+: 365.1651.
61. 2-(1H-Indol-5-yl)-pentan-3-one:
Yield 45%, 54 mg. X=Br, brown oil.
1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.52 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.22 –
7.18 (m, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.53 (s, 1H), 3.88 (q, J = 6.9 Hz, 1H), 2.70 – 2.14 (m, 2H), 1.48 (d, J = 8.1 Hz, 3H), 0.98 (t, J = 7.8 Hz, 3H).
13C NMR (101 MHz, CDCl3): δ 212.9, 134.9, 132.2, 128.2, 124.9, 121.7, 119.7, 111.5, 102.2,
52.7, 34.0, 17.9, 8.0.
HRMS (EI+): m/z calcd for C13H16NO: 202.1226, found [M+H]+: 202.1225. OHN
OHN
H N
62. 2-(4-(Methylsulfonyl)phenyl)-1-phenylpropan-1-one:
Yield 92%, 159 mg. X=Cl.
For characterisation, see entry 46, Chapter 2.
63. 2-(4-(Dimethylamino)phenyl)-1-phenylpropan-1-one:27
Yield 92%, 140 mg. X=Br, pale yellow solid.
H NMR (400MHz, CDCl3) : δ 7.97 (m, 2H), 7.46 (m, 1H), 7.37 (m, 2H), 7.16 (m, 2H), 6.67
(m, 2H), 4.60 (q, J = 6.8 Hz, 1H), 2.90 (s, 6H), 1.51 (d, J = 6.8 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 200.7, 149.3, 136.7, 132.5, 129.1, 128.7, 128.4, 128.4, 113.04,
46.8, 19.4.
Analytical data matches previously reported characterisation.
64. 2-(4-(Methylsulfonyl)phenyl)-1-(4-(trifluoromethyl)phenyl)propan-1-one:
Yield 88%, 188 mg. X=Cl, brown solid.
1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.1 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 4.79 (q, J = 6.9 Hz, 1H), 2.99 (s, 3H), 1.52 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 198.3, 146.7, 139.3, 138.5, 134.7, 134.4, 134.2 (q, J = 32.8 Hz), 134.0, 133.7, 128.9, 128.7, 128.0, 127.4, 127.4, 127.3, 127.3, 125.6, 125.6 (d, J = 3.5 Hz), 125.6, 124.6, 123.3 (q, J = 272.8 Hz), 121.9, 119.2, 119.2, 47.7, 44.1, 19.1. 19F NMR (377 MHz, CDCl3) δ -63.18.
HRMS (EI+): (m/z): [M+H]+ calcd for C17H16F3O3S, 357.0775; found, 357.0775
65. 2-(4-(Dimethylamino)phenyl)-1-(4-methoxyphenyl)propan-1-one:
Yield 95%, 162 mg. X=Br, yellow solid.
1H NMR (400 MHz, CDCl3) δ 8.03 – 7.92 (m, 2H), 7.17 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.9 Hz, 2H), 6.67 (d, J = 8.7 Hz, 2H), 4.57 (q, J = 6.8 Hz, 1H), 3.79 (s, 3H), 2.89 (s, 6H), 1.51 (s, O SO2 O N O F3C SO2 O O N
13C NMR (101 MHz, CDCl3) δ 199.2, 162.9, 149.3, 130.9, 129.5, 129.5, 128.2, 113.4, 112.87,
55.2, 46.4, 40.4, 19.4.
HRMS (EI+): m/z calcd for C18H22NO2: 284.1645, found [M+H]+: 284.1641.
66. 6-methoxy-2-(4-(Methylsulfonyl)phenyl)-3,4-dihydronaphthalen-1(2H)-one:28
Yield 63%, 124 mg. X=Cl, brown solid.
1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 6.87 (dd, J = 8.8, 2.5 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 3.88 (s, 3H), 3.87-3.83 (m, 1H), 3.19-3.08 (m, 1H), 3.05 (s, 3H) 3.04-2.96 (m, 1H), 2.41 (td, J = 9.2, 7.9, 4.4 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 195.7, 163.9, 146.6, 146.3, 138.9, 130.3, 129.6, 127.5, 125.95, 113.5, 112.6, 77.3, 55.5, 54.2, 44.6, 31.2, 29.3.
Analytical data matches previously reported characterisation. 67. 2-(1-Benzyl-1H-indol-5-yl)-1-phenylpropan-1-one:
Yield 83%, 177 mg. X=Br, brown solid.
1H NMR (400 MHz, CDCl3) δ 8.01 (m, 2H), 7.56 (d, J = 1.5 Hz, 1H), 7.47 – 7.39 (m, 1H),
7.38 – 7.33 (m, 2H), 7.32 – 7.26 (m, 3H), 7.26 – 7.20 (m, 1H), 7.15 – 7.05 (m, 4H), 6.49 (dd,
J = 3.1, 0.7 Hz, 1H), 5.26 (s, 2H), 4.78 (q, J = 6.8 Hz, 1H), 1.58 (d, J = 6.8 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 200.8, 137.3, 136.7, 135.4, 132.6, 132.5, 129.1, 128.8, 128.72,
128.7, 128.3, 127.6, 126.9, 121.7, 119.9, 110.2, 101.5, 50.1, 47.9, 19.9.
HRMS (EI+): m/z calcd for C24H22NO: 340.1696, found [M+H]+: 340.1695.
68. 1-Phenyl-2-(quinolin-6-yl)propan-1-one:
Yield 83%, 130 mg. X=Cl, colourless oil.
1H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 2.8 Hz, 1H), 8.13 – 7.99 (m, 2H), 8.01 – 7.94 (m,
2H), 7.69 (m, 2H), 7.51 – 7.42 (m, 1H), 7.41 – 7.31 (m, 3H), 4.89 (q, J = 6.9 Hz, 1H), 1.62 (d, J = 6.9 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 199.9, 150.2, 147.2, 139.8, 136.2, 135.9, 133.0, 130.1, 129.76,
128.7, 128.5, 128.4, 126.1, 121.3, 47.6, 19.5.
HRMS (EI+): m/z calcd for C18H16NO: 262.1226, found [M+H]+: 262.1226. O
O
SO2
O N
69. 1,2-Diphenyl-2-(quinolin-6-yl)ethan-1-one:29
Yield 65%, 126 mg. X=Cl, brown solid.
1H NMR (400 MHz, CDCl3) δ 8.88 (dd, J = 4.2, 1.5 Hz, 1H), 8.12 – 8.00 (m, 4H), 7.71 –
7.64 (m, 2H), 7.52 (t, J = 7.3 Hz, 1H), 7.41 (t, J = 7.7 Hz, 2H), 7.37 – 7.32 (m, 5H), 7.28 (dd,
J = 10.3, 6.0 Hz, 1H), 6.25 (s, 1H).
13C NMR (101 MHz, CDCl3) δ 197.9, 150.3, 147.3, 138.4, 137.6, 136.5, 136.0, 135.1, 133.19,
131.0, 129.7, 129.1, 128.9, 128.9, 128.6, 128.1, 127.5, 127.4, 126.4, 121.8, 121.2, 59.1. Analytical data matches previously reported characterisation.
70. 1-Phenyl-2-(quinolin-5-yl)propan-1-one:
Yield 95%, 149 mg. X=Cl, colourless oil.
1H NMR (400 MHz, CDCl3) δ 9.28 (d, J = 0.7 Hz, 1H), 8.65 (d, J = 6.1 Hz, 1H), 7.97 (d, J =
6.4 Hz, 1H), 7.90-7.81 (m, 3H), 7.55-7.39 (m, 3H), 7.36-7.26 (m, 2H), 5.33 (q, J = 6.8 Hz, 1H), 1.64 (d, J = 6.9 Hz, 2H).
13C NMR (101 MHz, CDCl3) δ 200.1, 153.7, 143.9, 137.2, 136.0, 133.4, 133.0, 129.3, 129.2,
128.6, 128.5, 127.2, 127.1, 115.6, 43.0, 18.5.
HRMS (EI+): m/z calcd for C18H16NO: 262.1226, found [M+H]+: 262.1225.
71. 1-Phenyl-2-(6-(trifluoromethyl)176yridine-2-yl)propan-1-one:
Yield 74%, 125 mg. X=Cl, yellow solid.
1H NMR (400 MHz, CDCl3) δ 8.06 (dd, J = 8.4, 1.2 Hz, 2H), 7.78 (t, J = 7.8 Hz, 1H), 7.55
– 7.36 (m, 5H), 5.08 (q, J = 7.0 Hz, 1H), 1.62 (d, J = 7.0 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 199.2, 161.6, 138.1, 136.0, 133.3, 129.0, 128.6, 124.7, 118.58
(q, J= 2.7 Hz), 50.4, 18.0. Trifluoromethyl carbon was not detected.j
19F NMR (377 MHz, CDCl3) δ -68.04.
HRMS (EI+): m/z calcd for C15H13 F3NO: 280.0939, found [M+H]+: 280.0944.
O N
O
N
O
72. 2-(4-Nitrophenyl)-1-phenylpropan-1-one:30
Yield 58%, 89 mg. X=Cl, yellow oil.
1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.7 Hz, 2H), 7.93 (dt, J = 8.5, 1.6 Hz, 2H), 7.57 –
7.45 (m, 3H), 7.41 (t, J = 7.7 Hz, 2H), 4.84 (q, J = 6.9 Hz, 1H), 1.58 (d, J = 6.9 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 199.1, 148.6, 146.9, 135.8, 133.3, 128.7, 124.1, 47.3, 46.6,
44.5, 21.2, 20.3, 19.3, 19.0.
Analytical data matches previously reported characterisation. 73. 4-(1-Oxo-1-phenylpropan-2-yl)benzonitrile:31
Yield 19%, 27 mg. X=Cl, yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.95 – 7.88 (m, 1H), 7.62 – 7.56 (m, 1H), 7.56 – 7.50 (m,
0H), 7.45 – 7.38 (m, 2H), 4.77 (q, J = 6.9 Hz, 0H), 1.55 (d, J = 6.9 Hz, 1H).
13C NMR (101 MHz, CDCl3) δ 199.2, 146.6, 135.9, 133.3, 132.7, 128.7, 128.6, 118.6, 110.93,
47.6, 19.3.
Analytical data matches previously reported characterisation.
75. 2-(10-(3-(4-Methylpiperazin-1-yl)propyl)-10H-phenothiazin-2-yl)-1- phenylpropan-1-one:
Yield 86%, 248 mg. X=Cl, brown oil.
1H NMR (400 MHz, CDCl3) δ 7.96-7.90 (m, 2H), 7.50 -7.44 (m, 1H), 7.40-7.34 (m, 2H), 7.14-7.06 (m, 2H), 7.03 (d, J = 7.8 Hz, 1H), 6.90-6.83 (m, 3H), 6.72 (d, J = 1.6 Hz, 1H), 4.61 (q, J = 6.8 Hz, 2H), 2.58-2.15 (m, 13 H), 3.86 (t, J = 6.9 Hz, 2H), 1.85 (p, J = 7.0 Hz, 1H), 1.50 (d, J = 6.8 Hz, 3H) 13C NMR (101 MHz, CDCl3) δ 200.1, 145.7, 145.0, 140.7, 136.3, 132.9, 128.7, 128.5, 127.71, 127.3, 127.2, 124.9, 123.7, 122.4, 122.0, 115.6, 114.5, 55.4, 55.1, 53.1, 47.6, 46.0, 45.2, 24.2, 19.5.
HRMS (EI+): m/z calcd for C29H34N3OS: 472.2417, found [M+H]+: 472.2408.
O NO2 O CN O S N N N
79. (S)-2-[(t-Butoxycarbonyl)amino]-3-(5-(1-oxo-1-phenylpropan-2-yl)-1H-indol-3- yl)propanoic acid:
Yield 87%, 56 mg. X=Br, brown solid.
1H NMR (400 MHz, CD3OD) δ 10.28 (s, 1H), 8.00 (d, J = 7.4 Hz, 2H), 7.55-7.49 (m, 1H),
7.45 (t, J = 7.3 Hz, 1H), 7.37 (t, J = 7.5 Hz, 2H), 7.24 (d, J = 8.3 Hz, 1H), 7.06 (s, 1H), 6.97 (t,
J = 7.7 Hz, 1H), 4.86-4.83 (m, partly covered by the signal of water, 1H), 4.41 (td, J = 8.0, 5.2 Hz, 1H), 3.26 (dd, J = 14.5, 5.4 Hz, 1H), 3.10 (dd, J = 15.4, 7.3 Hz, 1H), 1.53 (d, J = 6.7 Hz, 3H), 1.39 (d, J = 1.9 Hz, 9H).
13C NMR (101 MHz, CD3OD) 203.2, 176.0, 157.8, 138.1, 133.7, 133.3, 129.9, 129.4, 129.4,
125.2, 122.2, 118.7, 112.8, 111.1, 80.5, 55.9, 49.3, 48.4, 28.7, 23.7, 20.3. One aromatic carbon was not detected.
[α] 20D = -30.2 (c= 0.5, MeOH)
HRMS (EI+): m/z calcd for C25H29N2O5: 437.2071, found [M+H]+: 437.2071.
81. (S)-2-[(t-Butoxycarbonyl)amino]-3-(6-(1-oxo-1-phenylpropan-2-yl)-1H-indol-3- yl)propanoic acid:
Yield 70%, 45 mg. X=Cl, brown solid.
1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 7.4 Hz, 2H), 7.55-7.41 (m, 2H), 7.36 (t, J = 7.6
Hz, 2H), 7.22 (s, 1H), 7.03 (s, 1H), 6.96 (d, J = 8.3 Hz, 1H), 4.86-4.83 (m, partly covered by the signal of water, 1H), 4.41-4.32 (m, 1H), 3.29-3.20 (m, 1H), 3.07 (dd, J = 14.6, 7.9 Hz, 1H), 1.50 (d, J = 6.8 Hz, 3H), 1.32 (d, J = 4.3 Hz, 9H).
13C NMR (101 MHz, CDCl3) δ 203.0, 176.0, 157.7, 138.4, 138.1, 136.1, 133.7, 129.9, 129.44,
128.0, 124.8, 120.0, 119.9, 111.3, 111.1, 80.4, 56.0, 49.3, 28.7, 28.6, 20.1. [α] 20D = -2.2 (c= 0.5, MeOH)
HRMS (EI+): m/z calcd for C25H29N2O5: 437.2071, found [M+H]+: 437.2071.
O NH HOOC BocHN O N H COOH NHBoc
83. (S)-2-[(t-Butoxycarbonyl)amino]-3-(6-(1-oxo-1-phenylpropan-2-yl)-1H-indol-3- yl)propanoic acid:
Yield 94%, 60 mg. X=Br, yellow solid.
1H NMR (400 MHz, CDCl3) δ 10.57 (s, 1H), 7.92 (d, J = 7.8 Hz, 2H), 7.44 (dd, J = 7.5, 5.1
Hz, 2H), 7.31 (t, J = 7.7 Hz, 2H), 7.19 (s, 1H), 6.91 (t, J = 7.6 Hz, 1H), 6.79 (d, J = 7.3 Hz, 1H), 5.15 (q, J = 6.7 Hz, 1H), 4.47-4.34 (m, 1H), 3.29-3.28 (m, partly covered by the signal of deuterated methanol, 1H), 3.11 (dd, J = 14.7, 8.0 Hz, 1H), 1.53 (dd, J = 6.7, 1.3 Hz, 3H), 1.36 (d, J = 6.5 Hz, 9H).
13C NMR (101 MHz, CDCl3) δ 202.2, 175.8, 157.8, 137.8, 134.0, 130.0, 129.5, 129.5, 125.8,
125.0, 124.8, 121.0, 120.5, 118.5, 112.2, 80.5, 55.9, 49.3, 44.7, 28.8, 28.7, 18.2. One aromatic carbon was not detected.
[α] 20D = +23.4 (c= 0.5, MeOH)
HRMS (EI+): m/z calcd for C25H29N2O5: 437.2071, found [M+H]+: 437.2071.
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Appendix: scientific contributions
Publications
“Computational studies on the mechanism of the Ni-catalysed carboxylation of boronate”. M. Delarmolina,E. Marelli,S. P. Nolan,M. Buehl, manuscript in preparation.
“Living GenoChemetics: Hyphenating Synthetic Biology and Synthetic Chemistry in vivo”. S. V. Sharma,X. Tong, C. Pubill-Ulldemolins, C. Cartmell, E. J. A. Bogosyan,E. J. Rackham, E. Marelli,R. B. Hamed,& R. J. M. Goss, Nature Comm.,
manuscript accepted.
“Mild, Aqueous α-Arylation of Ketones: Towards New Diversification Tools for
Halogenated Metabolites and Drug Molecules”. E. Marelli, Y. Renault, S. V Sharma, S.
P. Nolan, R. J. M. Goss, Chem. – Eur. J. 2017, 23, 3832–3836.
“α-Arylation of Imines Leading to N-Unprotected Indoles and Azaindoles”. E. Marelli, M. Corpet, Y. Minenkov, R. M. Neyyappadath, A. Bismuto, G. Buccolini, M. Curcio, L. Cavallo, S. P. Nolan, ACS Catal. 2016, 6, 2930–2938.
“Arylation of Amines in Alkane Solvents by using Well-Defined Palladium–N- Heterocyclic Carbene Complexes”. E. Marelli, A. Chartoire, G. Le Duc, S. P. Nolan,
ChemCatChem 2015, 7, 4021–4024.
“Synthesis of (diarylmethyl)amines using Ni-catalyzed arylation of C(sp3)-H bonds”. J. Fernandez-Salas, E. Marelli, S. P. Nolan, Chem. Sci. 2015, 4973–4977.
“Synthesis of an Intermediate of Nafoxidine via Nickel-Catalyzed Ketone Arylation”. E. Marelli, J. A. Fernández Salas, S. P. Nolan, Synthesis (Stuttg). 2015, 47, 2032–2037.
“General and Mild Ni0-Catalyzed α-Arylation of Ketones Using Aryl Chlorides”.
E. Marelli, J. A. Fernández-Salas, D. B. Cordes, A. M. Z. Slawin, S. P. Nolan, Chem. – Eur. J. 2015, 21, 3906–3909.
“Palladium-Catalyzed α-Arylation of Arylketones at Low Catalyst Loadings”.
E. Marelli, M. Corpet, S. R. Davies, S. P. Nolan, Chem. – Eur. J. 2014, 20, 17272–17276.
“Nickel-catalysed carboxylation of organoboronates”. Y. Makida, E. Marelli, A.
Communication in conferences
“Ni-Catalysed Carboxylation of Organoboron Reagents”. USIC 2, Glasgow, 5th
Sep 2014 – Oral Presentation
“Ni-Catalysed Carboxylation of Organoboron Reagents”. CRITICAT
Environment Day, Harwell Catalysis Hub meeting, 22nd Jan 2015 – Oral Presentation
“Nickel catalysed deprotonative cross coupling reactions: a valuable alternative to palladium”. OMCOS 18, 28th June to 2nd July 2015 – Poster Presentation
“Synthetic utility and mechanism of Nickel-catalysed deprotonative cross
couplings”. Postgraduate Symposiums 2015, St Andrews, 7th Dec 2015 – Oral
Presentation
“Development of efficient and user friendly protocols for Palladium-catalysed carbonyl arylation”. Postgraduate Symposiums 2015, St Andrews, 7th Dec 2016 – Oral Presentation
“Development of efficient and user friendly protocols for palladium-catalysed α- arylation of carbonyls”. Halogenase Network Meeting, St Andrews, 17th Mar 2017 – Oral Presentation
Statement of collaborations
The scope of the reaction discussed in Chapter 2 was studied in collaboration with Ms Sian R. Davies and Dr. Martin Corpet.
The methodology discussed in Chapter 3 was developed in collaboration with Dr. Martin Corpet. The scope of the reaction was studied in collaboration with Mr Alessandro Bismuto, Ms Giulia Buccolini, Mr Massimiliano Curcio and Mr Rifahath Mon. The computational experiments were carried out by Yuri Minenkov (from the group of Luigi Cavallo).
The scope of the reaction discussed in Chapter 4, as well as its mechanism, were studied in collaboration with Dr. Josè A. Fernàndez-Sàlas. The X-Ray experiments were carried out by David B. Cordes.
The methodology discussed in Chapter 5 was developed in collaboration with Dr. Josè A. Fernàndez-Sàlas.
The scope of the reaction discussed in Chapter 6 was studied in collaboration with Mr Yohann Renault. Marfey’s test was carried out in collaboration with Dr. Sunil V. Sharma.