˚
O. Aberg et al.
warm to room temperature and stirred overnight. The reaction Ar-H), 7.44 (2 H, AA0XX0, Ar-H), 6.99 (1 H, m, Ar-H), 6.71 (2 H, br s,
mixture was cooled to 01C and acidified to pH 2 with 2 M HCl, NH2), 3.53–3.40 (4 H, m, N(CH2CH3)2), 2.78 (2 H, dd, J = 7.1, 0.8 Hz,
prior to extraction with EtOAc and washed with brine and water. CH2), 1.99 (1 H, m, J = 6.6 Hz, CH), 1.21 (6 H, m, N(CH2CH3)2), 1.03
The organic layer was dried (MgSO4), filtered and evaporation of (6 H, d, J = 6.6 Hz, 2 ꢂ CH3) ppm. 13C NMR (100 MHz, acetone-d6)
the solvent yielded the crude product 2 as a brown oil with an d: 171.8, 148.7, 143.8, 139.2, 138.9, 137.2, 131.4, 130.7, 127.9,
1
estimated purity of 495% as confirmed by H-NMR, which was 40.1, 32.0, 23.2, 15.2, 13.9 ppm.
used in the next step without further purification. LC-MS (ESI1)
m/z: 320.1 (M1H1).
General procedure for deprotection and acylation exemplified with
butyl 3-(4-iodophenyl)-5-isobutylthiophen-2-ylsulphonylcarbamate (4a)
General procedure of the Suzuki-coupling exemplified by N-(tert-
butyl)-3-(4-iodophenyl)-5-isobutylthiophene-2-sulphonamide (2a)
Compound 2a (76 mg, 0.16 mmol) was dissolved in dry CH2Cl2
(5 ml) and cooled to 01C under nitrogen. To the solution was
added BCl3 (1 ml) as 1.0 M in hexane. After 1 h, the reaction
A Smith Process VialTM (2–5 ml) was charged with crude boronic
acid
1 (152 mg, 0.46 mmol), 1,4-diiodobenzene (188 mg,
mixture was co-evaporated four times with CHCl3. The residue
was dissolved in CH2Cl2 (5 ml), thereafter triethylamine (88 ml,
0.64 mmol) and n-butyl chloroformate (24.5 ml, 0.19 mmol) was
added and the reaction mixture was stirred for 2 h at room
temperature. The reaction mixture was diluted with CH2Cl2 and
washed with water and brine. The organic layer was dried
(MgSO4) and evaporated prior to purification by column
chromatography (first pure isohexane, then 3:1 isohexane:
EtOAc), to yield 4a as white crystals (38 mg, 0.07 mmol, 44%).
1H NMR (400 MHz, CDCl3) d: 7.75 (2 H, AA0XX0, Ar-H), 7.34 (1 H, br
s, NH), 7.21 (2 H, AA0XX0, Ar-H), 6.74 (1 H, m, Ar-H), 4.05 (2 H, t,
J = 6.5 Hz, OCH2), 2.71 (2 H, d, J = 7.1, 0.7 Hz, Ar-CH2), 1.94 (1 H, m,
J = 6.6 Hz, CH), 1.52 (2 H, m, CH2), 1.27 (2 H, m, J = 7.3 Hz, CH2),
0.99 (6 H, d, J = 6.6 Hz, 2 ꢂ CH3), 0.89 (3 H, t, J = 7.3 Hz, CH3) ppm.
13C NMR (100 MHz, CDCl3) d: 152.2, 150.3, 145.6, 137.7, 133.7,
130.9, 129.5, 129.4, 95.2, 67.3, 39.5, 30.8, 30.6, 22.5, 19.0,
13.9 ppm. Found: C, 42.37; H, 4.57; N, 2.50. Calc. for C19H24I-
NO4S2 ꢀ H2O: C, 42.30; H, 4.86; N, 2.60%.
0.57 mmol), 2.0 ml DME, 0.5 ml ethanol, 0.5 ml water and 0.5 ml
Na2CO3 (2 M, 1 mmol) and Pd(PPh3)4 (21.6 mg, 0.020 mmol) and
microwave irradiated for 10 min at 1101C. The reaction mixture
was extracted with CH2Cl2 and washed with brine and water,
prior to drying (MgSO4) and evaporation of solvent. The crude
product was purified by column chromatography (first pure
isohexane then isohexane:EtOAc 9:1) as white crystals in
quantitative yield (221 mg, 0.46 mmol) based on boronic acid
1.1H NMR (400 MHz, CDCl3) d: 7.76 (2 H, AA0XX0, Ar-H), 7.35 (2 H,
AA0XX0, Ar-H), 6.72 (1 H, s, Ar-H), 4.15 (1 H, br s, NH), 2.67 (2 H, dd,
J = 7.1, 0.8 Hz, CH2), 1.96–1.86 (1 H, m, J = 6.7 Hz, CH), 1.03 (9 H, s,
3 ꢂ CH3), 0.97 (6 H, d, J = 6.7 Hz, 2 ꢂ CH3) ppm. 13C NMR
(100 MHz, CDCl3) d: 149.1, 142.5, 137.9, 137.1, 134.8, 131.2, 129.1,
94.8, 55.1, 39.6, 30.9, 29.9, 22.5 ppm. Found: C, 45.42; H, 5.17; N,
2.87. Calc. for C18H24INO2S2: C, 45.28; H, 5.17; N, 2.87%.
4-(2-(N-tert-Butylsulphamoyl)-5-isobutylthiophen-3-yl)-N,N-diethyl-
benzamide (2b). Same procedure as for 2a
N-Butoxycarbonyl-3-[4-(N,N-diethylcarbamoyl)phenyl]-5-isobutyl-
thiophene-2-sulphonamide (4b)
Column chromatography (first isohexane, then 4:1 isohexane:
EtOAc, then 2:1 isohexane:EtOAc) yield 66% as off-white crystals.
1H NMR (400 MHz, acetone-d6) d: 7.75 (2 H, AA0XX0, Ar-H), 7.47 (2
H, AA0XX0, Ar-H), 6.99 (1 H, m, J = 0.9 Hz, Ar-H), 5.97 (1 H, br s,
NH), 3.66–3.22 (4 H, m, 2 ꢂ CH2), 2.80 (2 H, dd, J = 7.2 Hz, 0.9 Hz,
CH2), 2.04–1.97 (1 H, m, CH), 1.27 (6 H, m, N(CH2CH3)2), 1.08 (9 H,
s, 3 ꢂ CH3), 1.03 (6 H, d, J = 6.6 Hz, 2 ꢂ CH3) ppm. 13C NMR
(100 MHz, acetone-d6) d: 170.1, 149.0, 142.3, 137.6, 137.1, 136.0,
129.4, 129.3, 126.9, 54.9, 43.5, 39.7, 39.5, 30.8, 29.8, 22.5, 14.5,
13.2 ppm.
Purification by using column chromatography (first pure
isohexane, then 3:1 isohexane: EtOAc) and then RP-LC-MS yield
18% as white crystals. 1H and 13C NMR analyses were in
agreement with earlier published data.
Labelling chemistry
N-Butoxycarbonyl-3-[4-(N,N-diethyl[11C]carbamoyl)phenyl]-5-iso-
butylthiophene-2-sulphonamide ([11C]4b)
General procedure of the deprotection exemplified by 3-(4-
iodophenyl)-5-isobutylthiophene-2-sulphonamide (3a)
To a 800-ml vial was added aryl halide 4a (1.8 mg, 3.45 mmol) and
tetrakis(triphenylphosphine)palladium(0) (4.0 mg, 3.45 mmol). The
vial was capped and purged with argon before addition of 380 ml
of THF. The mixture was heated at 701C for 1 min and then kept
at room temperature for approximately 10 min before the
mixture was added to a purged vial containing diethylamine
(20 ml, 14.35 mg, 200 mmol). The mixture was injected onto a loop
(200 ml) and transferred to a 200-ml autoclave containing
[11C]carbon monoxide (10–100 nmol). The preheated autoclave
was pressurized by THF using an HPLC to 35 MPa and kept at
1101C for 5 min. The reaction mixture was ejected into a capped
and evacuated 5-ml vial, and the reactor was pressurized once
more with THF and ejected, and the radioactivity was measured.
The solvent was removed by purging with a flow of nitrogen at
701C for approx 1 min, and the radioactivity was measured again.
The residue was dissolved again by the addition of 1 ml
acetonitrile and an aliquot was withdrawn and analysed using
analytical UV-radio-HPLC. Rt = 8.2 min, isocratic 40%A, 60%B. The
To a cooled (01C) solution of 2a (65.2 mg, 0.14 mmol) in dry
CH2Cl2 (5 ml) under a nitrogen atmosphere BCl3 was added
(1 ml, 0.55 mmol) over 10 min. After stirring for 1 h at room
temperature, the reaction mixture was co-evaporated four times
with CHCl3. The crude product was purified by column
chromatography (first pure isohexane, then 3:1 isohexane:
EtOAc) and isolated as white crystals in 63% yield (33 mg,
0.08 mmol). 1H NMR (400 MHz, CDCl3) d: 7.79 (2 H, AA0XX0, Ar-H),
7.35 (2 H, AA0XX0, Ar-H), 6.77 (1 H, s, Ar-H), 4.74 (2 H, br s, NH2),
2.70 (2 H, dd, J = 7.1, 0.8 Hz, CH2), 1.94 (1 H, m, J = 6.7 Hz, CH),
1.01 (6 H, d, J = 6.7 Hz, 2 ꢂ CH3) ppm.
N,N-Diethyl-4-(5-isobutyl-2-sulphamoylthiophen-3-yl)benzamide
(3b). Same procedure as for 3a
The crude product was used in the next step without further
1
purification. H NMR (400 MHz, acetone-d6) d: 7.73 (2 H, AA0XX0,
Copyright r 2010 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2010, 53 616–624