J.W. Barlow, J.J. Walsh / European Journal of Medicinal Chemistry 45 (2010) 25–37
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column chromatography on silica gel (eluant: pet ether:ethyl
acetate, 5:1) to yield the amine as a mixture of diastereomers (4.3 g,
72%), with the following physical properties: IR (KBr, n) 2933, 1702,
(quat. C), 138.1 and 138.5 (quat. C), 138.5 ꢂ 2 (quat. C), 156.3 and
156.6 (quat. C), 204.3 and 204.4 (C]O); MS, m/z, (RI) 318 (M þ 1, 5),
188 (100), 131 (61), 103 (22); HRMS (M þ Na)þ 340.1671,
C22H23NONa requires 340.1677.
1602, 1467, 1280, 1132 cmꢀ1; 1H NMR (CDCl3, 400 MHz) dppm ¼ 1.60
(m,1H, NH),1.85–2.20 (m, 4H, ArCH2CH2CH2), 2.60 (m,1H, CH2), 2.79
(m, 1H, CH2), 2.91 (m, 1H, CH2), 3.10 (m, 1H, CH2), 4.00 and 4.08
(2 ꢂ m,1H, CH), 4.57 and 4.64 (2 ꢂ m,1H, CH), 7.16 (m, 3H, 3 ꢂ Ar-H),
7.32–7.45 (m, 2H, 2 ꢂ Ar-H), 7.61–7.80 (m, 3H, 3 ꢂ Ar-H); 13C NMR
dppm ¼ 18.3 and 18.5 (CH2), 27.6 and 28.6 (CH2), 29.0 and 30.0 (CH2),
45.8 and 46.7 (CH2CO), 52.9 and 54.6 (CH), 53.5 and 55.0 (CH),
122.8 ꢂ 2 (tert. C), 125.3 and 125.5 (tert. C), 125.5 and 125.6 (tert. C),
126.5 and 126.6 (tert. C), 128.1 ꢂ2 (tert. C), 128.3 and 128.4 (tert. C),
128.7 and 128.8 (tert. C),134.4 ꢂ 2 (tert. C),136.0 and 136.4 (quat. C),
137.0 and 137.1 (quat. C), 138.4 and 138.6 (quat. C), 156.2 and 156.5
(quat. C), 204.2 ꢂ 2 (C]O); MS, m/z, (RI) 278 (M þ 1, 4), 277 (Mþ, 2),
148 (85), 130 (100), 103 (26).
7.1.4. N1-(3-Oxo-2,3-dihydro-1H-1-indenyl)-N1-(1,2,3,4-
tetrahydro-1-naphthalenyl)acetamide (6c)
To a stirred solution of 5 (150 mg, 0.54 mmol) in CH2Cl2 (10 ml)
was added triethylamine (0.15 mL, 1.08 mmol), acetic anhydride
(0.10 mL, 1.08 mmol) and a catalytic quantity of DMAP. The reaction
was stirred overnight at room temperature, and the solvent
removed in vacuo. The residue was purified by flash column
chromatography on silica gel (eluant: pet ether:ethyl acetate, 3:1)
to yield the acetamide as white crystals (85 mg, 49%): Data for 1
pair of isomers: IR (KBr disc,
n); 2946, 1706, 1645, 1449, 1427,
1307 cmꢀ1
;
1H NMR (CDCl3, 400 MHz) dppm ¼ 1.94 (m, 2H, CH2),
2.08–2.28 (m, 5H, CH2 and CH3), 2.47 (m, 2H, CH2), 2.85 (m, 2H,
CH2), 3.20 (m, 1H, CH), 4.38 and 5.17 (2 ꢂ m, 1H, CH), 7.11–7.28 (m,
4H, 4 ꢂ Ar-H), 7.38 (dd, J1 ¼8.5 Hz, J2 ¼ 7.5 Hz, 1H, Ar-H), 7.48 (d,
J ¼ 7.5 Hz, 1H, Ar-H), 7.60 (dd, J1 ¼8.5 Hz, J2 ¼ 7.5 Hz, 1H, Ar-H), 7.73
(d, J ¼ 7.5 Hz,1H, Ar-H); 13C NMR dppm ¼ 21.7 (CH2), 23.7 (CH3), 29.0,
30.7, 30.7 (3 ꢂ CH2), 42.3, 53.8 (2 ꢂ CH), 123.0, 123.0, 123.0, 126.0,
127.3, 129.2, 134.0, 134.0 (8 ꢂ tert. C), 154.3 (NC]O), 202.6 (C]O).
HRMS (M þ Na)þ 342.1441, C21H22NO2 requires 342.1470.
7.1.2. 3-[Methyl(1,2,3,4-tetrahydro-1-naphthalenyl)amino]-1-
indanone (6a)
To a stirred solution of 5 (0.5 g, 1.81 mmol) in acetone (10 mL)
was added methyl iodide (0.56 ml, 9.05 mmol) and anhydrous
potassium carbonate (0.38 g, 2.75 mmol). The reaction was stirred
for 2 days at room temperature, filtered, and the solvent removed in
vacuo. The residue was purified by flash column chromatography
on silica gel (eluant: pet ether:ethyl acetate, 10:1) to yield the
amine as a yellow solid, with the following physical characteristics
7.1.5. 4-[(3-Oxo-2,3-dihydro-1H-1-indenyl)amino]-1,2,3,4-
tetrahydro-1-naphthalenone (8)
(0.34 g, 65%): IR (CCl4, n ;
) 2937, 2864, 1718, 1603, 1277, 1040 cmꢀ1
1H NMR (CDCl3, 400 MHz) dppm ¼ 1.56–2.21 (m, 4H, 2 ꢂ CH2), 1.88
and 2.28 (2 ꢂ s, 3H, CH3), 2.57–2.95 (m, 4H, CH2 and CH2CO), 4.01
and 4.09 (2 ꢂ dd, J1 ¼9.5 Hz, J2 ¼ 5 Hz, 1H, NCHCH2CH2), 4.51 and
4.74 (2 ꢂ dd, J1 ¼7 Hz, J2 ¼ 3.7 Hz, 1H, NCHCH2CO), 7.10–7.27 (m,
3H, 3 ꢂ Ar-H), 7.45 (m, 1H, Ar-H), 7.66–7.79 (m, 2H, 2 ꢂ Ar-H), 7.83–
7.97 (m, 2H, 2 ꢂ Ar-H). 13C NMR dppm ¼ 18.6 and 18.8 (CH2), 27.9 and
29.0 (CH2), 29.3 and 30.3 (CH2), 30.8 ꢂ 2 (CH3), 46.1 and 47.1
(CH2CO), 53.3 and 53.9 (CH), 54.9 and 55.4 (CH), 122.3 and 122.4
(tert. C), 125.38 and 125.42 (tert. C), 126.02 and 126.05 (tert. C),
126.05 and 126.10 (tert. C), 127.6 and 127.8 (tert. C), 127.9 and 128.0
(tert. C), 128.5 and 128.6 (tert. C), 134.4 ꢂ 2 (tert. C), 136.0 and 136.3
(quat. C), 137.0 and 137.1 (quat. C), 138.3 and 138.5 (quat. C), 156.1
and 156.4 (quat. C), 204.2 ꢂ 2 (C]O); MS, m/z, (RI) 292 (M þ 1,100),
291 (Mþ, 27), 221 (16), 198 (15), 162 (79); HRMS (M þ H)þ 292.1729,
C20H22NO requires 292.1701.
The reaction was carried out by reacting compound 3 (0.68 g,
3.23 mmol) with 7 (0.52 g, 3.23 mmol) in a manner similar to the
preparation of 5 using Et3N as base in CH2Cl2 to give 8 (0.39 g, 42%).
IR (CCl4, n
); 2955, 1702, 1676, 1600, 1462, 1340, 1285 cmꢀ1; 1H NMR
(CDCl3, 400 MHz) dppm ¼ 1.68 (m, 1H, NH), 2.14 and 2.30–2.41
(2 ꢂ m, 2H, CH2CH2CO), 2.51–2.63 (m, 2H, CH2CH2CO), 3.02–3.21
(m, 2H, CHCH2CO), 4.15 and 4.18 (2 ꢂ dd, J1 ¼5 Hz, J2 ¼ 3.5 Hz, 1H,
CH), 4.40 and 4.64 (2 ꢂ dd, J1 ¼6.7 Hz, J2 ¼ 3.5 Hz, 1H, CH), 7.33–
7.70 (m, 7H, 7 ꢂ Ar-H), 7.99 and 8.03 (2 ꢂ dd, J1 ¼7.5 Hz, J2 ¼1 Hz,
1H, COAr-H); 13C NMR dppm ¼ 26.9 and 29.5 (CH2CH2CO), 33.8 ꢂ 2
(CH2CH2CO), 45.4 and 45.7 (CHCH2CO), 53.3 and 53.5 (CH), 53.9 and
54.1 (CH), 122.7 and 122.8 (tert. C), 125.6 ꢂ 2 (tert. C), 126.8 and
127.2 (tert. C), 127.6 and 127.7 (tert. C), 127.7 and 127.9 (tert. C),
128.3 and 128.4 (tert. C), 131.7 and 131.8 (quat. C), 132.9 and 133.4
(tert. C),134.5 ꢂ 2 (tert. C),136.0 and 136.2 (quat. C),144.4 and 144.7
(quat. C), 155.4 and 155.7 (quat. C), 197.4 ꢂ 2 (C]O), 203.6 ꢂ 2
(C]O); MS, m/z, (RI) 292 (M þ 1, 23), 291 (Mþ, 86), 160 (42), 146
(93), 132 (100), 115 (69), 103 (73), 77 (62), 51 (29).
7.1.3. 3-[Allyl(1,2,3,4-tetrahydro-1-naphthalenyl)amino]-1-
indanone (6b)
To a stirred solution of 5 (0.5 g, 1.81 mmol) in acetone (10 mL)
was added allyl iodide (0.83 ml, 9.05 mmol) and anhydrous
potassium carbonate (0.38 g, 2.75 mmol). The reaction was stirred
for 2 days at room temperature, filtered, and the solvent removed in
vacuo. The residue was purified by flash column chromatography
on silica gel (eluant: pet ether:ethyl acetate, 10:1) to yield the
7.1.6. 4-[Methyl(3-oxo-2,3-dihydro-1H-1-indenyl)amino]-1,2,3,4-
tetrahydro-1-naphthalenone (9)
The reaction was carried out using compound 8 (100 mg,
0.34 mmol) in a manner similar to the preparation of 6a using
anhydrous potassium carbonate as a base to give 9 (68%): IR (CCl4,
amine as a yellow oil (0.24 g, 42%): IR (KBr disc, HCl salt,
n
) 2937,
n ;
); 2949, 2791, 1707, 1678, 1597, 1332, 1284, 1040 cmꢀ1 1H NMR
2523, 1602, 1438, 1278 cmꢀ1 1H NMR (CDCl3, 400 MHz)
;
(CDCl3, 400 MHz) dppm ¼ 1.99 and 2.19 (2 ꢂ s, 3H, CH3), 2.16 and
2.34 (2 ꢂ m, 2H, CH2CH2CO), 2.51–2.72 (m, 2H, CH2CO), 2.81 and
2.86 (2 ꢂ dd, J1 ¼12 Hz, J2 w 4 Hz,1H of CH2CO), 2.92–3.02 (m,1H of
CH2CO), 4.05 and 4.10 (2 ꢂ dd, J1 w 9 Hz, J2 ¼ 3.5 Hz, 1H,
CHCH2CH2), 4.52 and 4.64 (2 ꢂ dd, J1 ¼7 Hz, J2 ¼ 4 Hz, 1H,
CHCH2CO), 7.37–7.45 (m, 2H, 2 ꢂ Ar-H), 7.57–7.75 (m, 4H, 4 ꢂ Ar-H),
7.82 and 7.93 (2 ꢂ d, J ¼ 7.5 and 8 Hz, 1H, COAr-H), 8.03 (2 ꢂ dd,
J1 ¼8 Hz, J2 ¼1.5 Hz, 1H, COAr-H); 13C NMR dppm ¼ 25.6 and 25.7
(CH2CH2CO), 29.3 and 33.2 (CH3), 35.2 and 36.5 (CH2), 36.9 and 37.8
(CH2), 56.6 and 60.3 (CHCH2CO), 60.9 and 61.9 (CHCH2CH2), 122.6
and 122.7 (tert. C), 125.8 and 125.9 (tert. C), 127.1 and 127.2 (tert. C),
127.1 and 127.2 (tert. C), 127.5 and 127.7 (tert. C), 128.2 and 128.3
(tert. C),132.5 and 132.6 (quat. C),132.9 and 133.0 (tert. C),134.5 ꢂ 2
dppm ¼ 1.59–3.23 (m, 10H, 5 ꢂ CH2), 4.16 (m, 1H, CHCH2CH2), 4.51
and 4.66 (2 ꢂ m, 1H, CHCH2CO), 4.83 and 5.09 (2 ꢂ d, 1H, J ¼ 10 Hz,
1H, 1H of CH]CH2), 4.96 and 5.23 (2 ꢂ d, 1H, J ¼ 17.9 Hz, 1H, 1H of
CH]CH2), 5.65 and 5.85 (2 ꢂ m, 1H, CH]CH2), 7.09 (m, 1H, Ar-H),
7.15–7.31 (m, 2H, 2 ꢂ Ar-H), 7.43 (m, 1H, Ar-H), 7.64–7.82 (m, 3H,
3 ꢂ Ar-H), 7.90 and 8.08 (2 ꢂ d, J ¼ 7.5 Hz, 1H, COAr-H); 13C NMR
dppm ¼ 21.5 and 21.9, 25.1 and 27.6, 29.2 and 29.6 (CH2CH2CH2), 40.1
and 41.5 (NCH2), 47.8 and 49.4 (CH2CO), 55.0 and 57.0 (CH), 58.1 and
59.7 (CH),115.4 and 116.4 (CH]CH2),122.3 and 122.6 (tert. C),125.3
and 125.5 (tert. C), 125.9 and 126.0 (tert. C), 126.1 and 126.4 (tert. C),
127.1 and 127.8 (tert. C), 128.0 ꢂ 2 (tert. C), 128.5 and 128.6 (tert. C),
133.9 and 134.5 (tert. C), 136.6 and 137.4 (tert. C), 136.6 and 136.8