6834 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 21
Do¨rfler et al.
N-[N′-(4-Ethynylcyclohex-3-en-1-yl)-N′-propyl-4-aminobutyl]-4-
biphenylcarboxamide (4c). To a solution of 4a (23.9 mg; 0.05
mmol) in THF (5 mL), a 1 molar solution of tetrabutylammoni-
umfluoride (0.1 mL, 0.1 mmol) was added at -15 °C. After being
stirred at this temperature for 165 min, saturated aqueous NaHCO3
was added and the mixture was allowed to warm to room
temperature. The aqueous layer was extracted with CH2Cl2, and
the combined organic layers were dried (MgSO4) and evaporated.
The residue was purified by flash chromatography (CH2Cl2-MeOH
98:2) to give 4c as a colorless oil (13.2 mg, 65% yield). IR: 3491,
3352, 1655, 1427, 1346, 1257, 1130, 999, 945, 825 cm-1. 1H NMR
(360 MHz, CDCl3) δ 0.87 (t, 3 H, J ) 7.3 Hz), 1.41-1.73 (m, 7
H), 1.90 (m, 1 H), 2.04-2.34 (m, 4 H), 2.46 (m, 2 H), 2.56 (m, 2
H), 2.79-2.91 (m, 2 H), 3.49 (m, 2 H), 6.11-6.16 (m, 1 H), 6.56
(m, 1 H), 7.35-7.50 (m, 3 H), 7.58-7.68 (m, 4 H), 7.85 (m, 2 H).
13C (90 MHz, CDCl3) δ 11.82, 21.56, 24.79, 25.96, 27.44, 27.99,
30.03, 39.84, 50.03, 52.46, 55.67, 75.06, 84.78, 119.72, 127.17,
127.19, 127.43, 127.92, 128.88, 133.49, 135.05, 140.08, 144.13,
167.29. EIMS m/z 414. Anal. (C28H34N2O) C, H, N.
giving rise to a similar binding mode as dopamine and classical
dopamine receptor agonists.
Experimental Section
Chemistry. All reactions were carried out under nitrogen
atmosphere. Dry solvents and reagents were of commercial quality
and were used as purchased. MS were run on a Finnigan MAT
TSQ 700 spectrometer by EI (70 eV) with solid inlet. NMR spectra
were obtained on a Bruker Avance 360 or a Bruker Avance 600
spectrometer relative to TMS in the solvents indicated (J value in
Hz). IR spectra were performed on a Jasco FT/IR 410 spectrometer.
Purification by flash chromatography was performed using Silica
Gel 60 if not stated otherwise; TLC analyses were performed using
Merck 60 F254 aluminum sheets and analyzed by UV light (254
nm) in the presence of iodine or by spraying with ninhydrin reagent.
Preparative and analytical HPLC was performed on Agilent 1100
HPLC systems employing a VWL detector. CHN elementary
analyses were performed at the chair of Organic Chemistry of the
Friedrich Alexander University Erlangen-Nu¨rnberg or at Beetz,
Mirkroanalytisches Laboratorium Kronach (compounds 3a, 3c).
N-[4-[4-(4-Biphenyl)triazol-1-yl]butyl]-N-propyl-N-[4-(2-trimeth-
ylsilylethynyl)cyclohex-3-en-1-yl]amine (5a). Compound 5a was
prepared according to 10a using a solution of 13 (17.6 mg, 0.03
mmol) in THF (5 mL), Cu(I)I (10.4 mg, 0.05 mmol) and
Pd(PPh3)2Cl2 (17.1 mg, 0.02 mmol) as well as NMe2Et (0.05 mL,
0.46 mmol) and TMS-acetylene (15 µL, 0.11 mmol). Stirring at
room temperature for 90 min, workup according to 10a, and
purification by flash chromatography (CH2Cl2-MeOH 98:2 and
hexane-EtOAc 4:1 + 0.5% NMe2Et) yielded 5a as a yellow solid
(6.6 mg, 41% yield). IR: 3766, 2841, 2646, 1676, 1583, 1502, 1412,
N-[N′-Propyl-N′-[4-(2-trimethylsilylethynyl)cyclohex-3-en-1-yl]-
4-aminobutyl]-4-biphenylcarboxamide (4a). A solution of 10a (32.5
mg, 0.10 mmol) in THF (4 mL) was added to PPh3 (130.7 mg,
0.50 mmol). After addition of H2O (1 mL), the mixture was stirred
at room temperature for 2 d. Then, the mixture was diluted with
Et2O (100 mL), dried (Na2SO4), and evaporated. After dissolving
the residue in CHCl3 (5 mL), Et3N (0.05 mL, 0.36 mmol) was added
and the mixture was cooled to 0 °C. Then, a solution of 4-biphenyl
carboxylic acid chloride (92.1 mg, 0.43 mmol) in CHCl3 (5 mL)
was added dropwise and the mixture was allowed to warm to room
temperature. After being stirred at this temperature for 3 h, saturated
aqueous NaHCO3 was added and the aqueous layer was extracted
with CH2Cl2. The combined organic layers were dried (Na2SO4)
and evaporated. The residue was purified by flash chromatography
(CH2Cl2-MeOH 98:2 and hexane-EtOAc 4:1 + 0.5% NMe2Et)
to give 4a as a colorless oil (15.8 mg, 33% yield). IR: 3352, 2954,
1030, 818 cm-1 1H NMR (360 MHz, CDCl3) δ 0.17 (s, 9 H),
.
0.85 (t, 3 H, J ) 7.3 Hz), 1.33-1.53 (m, 5 H), 1.81 (m, 1 H),
1.91-2.10 (m, 3 H), 2.12-2.28 (m, 3 H), 2.36 (m, 2 H), 2.47 (m,
2 H), 2.73 (m, 1 H), 4.43 (m, 2 H), 6.12 (m, 1 H), 7.35 (m, 1 H),
7.45 (m, 2 H), 7.61-7.69 (m, 4 H), 7.77 (s, 1 H), 7.91 (m, 2 H).
13C NMR (90 MHz, CDCl3) δ 11.82, 21.15, 25.03, 25.95, 28.24,
28.40, 30.29, 49.53, 50.43, 52.39, 55.23, 94.50, 106.53, 119.33,
120.64, 126.08, 126.98, 127.41, 127.51, 128.81, 129.72, 135.28,
140.64, 140.85, 147.47. EIMS m/z 510. Anal. (C32H42N4Si) C,
H, N.
2631, 2866, 2141, 1635, 1547, 1435, 1250, 1130, 1003, 841 cm-1
.
1H NMR (600 MHz, CDCl3) δ 0.17 (s, 9 H), 0.85 (t, 3 H, J ) 7.3
Hz), 1.38-1.49 (m, 3 H), 1.53 (m, 2 H), 1.66 (m, 2 H), 1.83 (m,
1 H), 2.02-2.10 (m, 1 H), 2.15-2.30 (m, 3 H), 2.39 (m, 2 H),
2.49 (m, 2 H), 2.77 (m, 1 H), 3.48 (m, 2 H), 6.12 (m, 1 H), 6.43
(m, 1 H), 7.39 (m, 1 H), 7.46 (m, 2 H), 7.60-7.67 (m, 4 H), 7.83
(m, 2 H). 13C NMR (150 MHz, CDCl3) δ 0.03, 11.83, 21.61, 24.87,
26.08, 27.44, 28.02, 30.13, 39.86, 50.00, 52.46, 55.68, 91.80,
106.27, 120.67, 127.18, 127.19, 127.43, 127.91, 128.88, 133.49,
135.30, 140.10, 144.12, 167.29. EIMS m/z 487. Anal.
(C31H42N2OSi) C, H, N.
N-[4-[4-(4-Biphenyl)triazol-1-yl]butyl]-N-propyl-N-[4-(2-phenyl-
ethynyl)cyclohex-3-en-1-yl]amine (5b). Compound 5b was prepared
according to the protocol of 10a using a solution of 13 (11.4 mg,
0.02 mmol) in THF (5 mL), Cu(I)I (7.8 mg, 0.04 mmol), and
Pd(PPh3)2Cl2 (12.2 mg, 0.02 mmol) as well as NMe2Et (0.05 mL,
0.46 mmol) and phenylacetylene (10 µL, 0.09 mmol). Stirring at
room temperature for 90 min, workup according to 10a, and
purification by HPLC (CH3CN-H2O + 0.1% TFA) yielded 5b as
a white solid (TFA salt, 5.8 mg, 14% yield). IR: 3409, 2924, 2852,
1683, 1483, 1441, 1200, 1136, 1034, 845, 802, 765, 726, 692 cm-1
.
1H NMR (360 MHz, CD3OD/CHCl3 1:1, TFA salt) δ 1.04 (t, 3 H,
J ) 7.3 Hz), 1.69-1.87 (m, 5 H), 2.06-2.20 (m, 3 H), 2.38-2.62
(m, 4 H), 3.01-3.21 (m, 4 H), 3.52 (m, 1 H), 4.59 (m, 2 H), 6.08
(m, 1 H), 7.29-7.41 (m, 6 H), 7.45 (m, 2 H), 7.61-7.73 (m, 4 H),
7.90 (m, 2 H), 8.25 (s, 1 H). 13C NMR (90 MHz, CD3OD/CHCl3
1:1, TFA salt) δ 11.25, 19.30 (HSQC), 22.73 (HSQC), 23.99, 26.83,
27.74, 29.66, 50.00, 50.97 (HSQC), 53.46 (HSQC), 59.92, 89.23,
121.80, 122.00, 123.76,126.75, 127.53, 128.25, 129.03, 129.53,
129.85, 132.08, 141.18, 142.16, 148.61. HR-EIMS m/z 514.3096;
purity HPLC.
N-[N′-Propyl-N′-[4-(2-phenylethynyl)cyclohex-3-en-1-yl]-4-ami-
nobutyl]-4-biphenylcarboxamide (4b). Compound 4b was prepared
according to the protocol of 4a using crude 10b (37 mg, ap-
proximately 0.11 mmol) in THF (4 mL), PPh3 (154.8 mg, 0.59
mmol), and H2O (1 mL).
For the acylation, CHCl3 (5 mL), Et3N (0.06 mL, 0.43 mmol),
and a solution of 4-biphenyl carboxylic acid chloride (125.0 mg,
0.58 mmol) in CHCl3 (5 mL) were used. Stirring at room
temperature for 24 h, workup according to 4a and purification by
HPLC (CH3CN-H2O + 0.1% TFA, gradient) yielded 4b as a white
solid (TFA salt, 2.6 mg, 4% yield (referring to 9 as starting
material)). IR: 3745, 3645, 3531, 3126, 2779, 2738, 2434, 2306,
N-[4-[4-(4-Biphenyl)triazol-1-yl]butyl]-N-propyl-N-(4-ethynylcy-
clohex-3-en-1-yl)amine (5c). Compound 5c was prepared according
to the procedure of 4c using a solution of 5a (13.4 mg; 0.03 mmol)
in THF (5 mL) and a 1 molar solution of tetrabutylammonium-
fluoride (0.05 mL, 0.05 mmol). Stirring at -15 °C for 150 min,
workup according to 4c, and purification by flash chromatography
(CH2Cl2-MeOH 98:2) and HPLC (CH3CN-H2O + 0.1% TFA)
yielded 5c as a white solid (TFA salt, 6.2 mg, 43% yield). IR: 3433,
3290, 2966, 2941, 2652, 2513, 1682, 1481, 1462, 1437, 1412, 1200,
1
2214, 1647, 1612, 1574, 1558, 1390, 1138, 1078 cm-1. H NMR
(360 MHz, CD3OD, TFA salt) δ 1.04 (t, 3 H, J ) 7.4 Hz),
1.71-1.96 (m, 7 H), 2.19 (m, 1 H), 2.44-2.66 (m, 4 H), 3.04-3.28
(m, 4 H), 3.51 (m, 2 H), 3.63 (m, 1 H), 6.09 (m, 1 H,), 7.29-7.41
(m, 6 H), 7.45 (m, 2 H), 7.62-7.45 (m, 4 H), 7.92 (m, 2 H). 13C
NMR (90 MHz, CD3OD, TFA salt) δ 11.24, 19.49, 19.69, 23.08,
23.26, 24.15, 24.24, 27.04, 27.15, 27.75, 29.91, 39.46, 51.77, 52.09,
53.61, 53.94, 60.42, 89.54, 89.64, 122.28, 124.27, 128.02, 128.05,
128.75, 129.05, 129.31, 129.39, 129.93, 130.32, 132.31, 133.92,
141.05, 145.79, 170.04. HR-EIMS m/z 490.2984; purity HPLC.
1
1130, 831, 768 cm-1. H NMR (360 MHz, CD3OD, TFA salt) δ
1.01 (t, 3 H, J ) 7.4 Hz), 1.67-1.88 (m, 5 H), 2.03-2.15 (m, 3
H), 2.34-2.58 (m, 4 H), 3.00-3.24 (m, 4 H), 3.26 (s, 1 H), 3.56