A New Family of N-Aryl Lactams Active on Chemesthesis and Taste
FULL PAPER
Compound 22: 1332.3 mg, 96%, white solid, m.p. 138 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.98 (m, 4 H, 2 CH2), 2.68 (m, 2 H,
6.85–7.17 (m, 4 H, Ar) ppm. MS: m/z (%) = 179 (55) [M + 1]+, 178
(100) [M+], 149 (10), 122 (80), 120 (20), 106 (5), 95 (15), 77 (15),
CH2CO), 3.75 (m, 2 H, CH2N), 6.90–7.75 (m, 4 H, Ar) ppm. 13C 65 (12), 52 (10).
NMR (CDCl3): δ = 20.7, 23.1, 32.3, 51.7, 119.7, 120.8, 124.9, 128.3,
Compound 31: 66.0 mg, 17%, grey solid, m.p. 188 °C. 1H NMR
131.7, 151.3, 171.8 ppm. HRMS (ESI): m/z = 214.08366 [M +
(300 MHz, CDCl3): δ = 2.12 (m, 2 H, CH2), 3.44 (t, J = 5.8, 2 H,
CH2N), 3.78 (t, J = 5.5, 2 H, CH2NHCO), 5.55 (br. s, 1 H, NH),
6.85–7.20 (m, 4 H, Ar) ppm. MS: m/z (%) 192 (60) [M+], 175 (10),
Na]+, 192.10194 [M + 1]+.
Compound 23: 202.1 mg, 88%, white solid, m.p. 172–173 °C. 1H
NMR (300 MHz, CDCl3): δ = 1.97 (m, 4 H, 2 CH2), 2.62 (m, 2 H,
CH2CO), 3.62 (m, 2 H, CH2N), 6.91 (m, 3 H, Ar), 7.21 (t, J =
7.90, 1 H, H-5) ppm. 13C NMR (CDCl3): δ = 20.9, 23.1, 32.3, 52.0,
114.5, 115.2, 116.0, 130.0, 143.1, 157.8, 171.1 ppm. MS: m/z (%) =
191 (100) [M+], 162 (15), 135 (70), 122 (62), 120 (15).
Compound 24: 315.8 mg, 80%, white solid, m.p. 241–242 °C. 1H
NMR (300 MHz, [D6]DMSO): δ = 1.79 (m, 4 H, 2 CH2), 2.30 (m,
2 H, CH2CO), 3.46 (m, 2 H, CH2N), 6.69 (d, 2 H, J = 8.0, H-2
and H-6), 7.00 (d, 2 H, J = 8.0, H-3 and H-5), 9.39 (s, 1 H, OH)
ppm. 13C NMR ([D6]DMSO): δ = 21.2, 23.3, 32.7, 51.5, 115.4 (two
signals overlapping), 127.6 (two signals overlapping), 135.3, 155.7,
168.8 ppm. MS: m/z (%) = 191 (100) [M+], 162 (90), 135 (60), 122
(75), 120 (20), 107 (10), 93 (15).
Compound 25: 716.3 mg, 86%, white solid, m.p. 154–155 °C. 1H
NMR (300 MHz, [D6]DMSO): δ = 1.68 (br., 6 H, 3 CH2), 2.52 (m,
2 H, CH2CO), 3.48 (m, 2 H, CH2N), 6.73 (dt, J = 8.0, 0.9, 1 H,
H-5), 6.84 (dd, J = 8.0, 0.9, 1 H, H-3), 6.98 (dd, J = 8.0, 0.9, 1 H,
H-6), 7.04 (dt, J = 8.0, 0.9, 1 H, H-4), 9.32 (s, 1 H, OH) ppm. 13C
NMR ([D6]DMSO): δ = 23.2, 28.9, 29.5, 37.6, 54.3, 120.1, 121.1,
124.3, 127.9, 133.4, 150.9, 177.2 ppm. MS: m/z (%) = 205 (100)
[M+], 188 (20), 177 (20), 162 (5), 148 (35), 122 (90), 120 (60), 109
(40).
Compound 26: 186.8 mg, 88%, white solid, m.p. 136–137 °C. 1H
NMR (300 MHz, CDCl3): δ = 1.82 (br., 4 H, 3 CH2), 2.72 (m, 2
H, CH2CO), 3.73 (m, 2 H, CH2N), 6.65 (m, 3 H, Ar), 7.18 (t, J =
7.9, 1 H, H-5) ppm. 13C NMR (CDCl3): δ = 23.3, 28.5, 29.8, 37.4,
53.5, 114.5, 114.8, 116.1, 130.0, 144.5, 157.7, 176.7 ppm. MS:
m/z (%) = 205 [M+, 90], 177 (20), 148 (50), 135 (25), 122 (100), 109
(18).
135 (15), 122 (100), 120 (40), 109 (20), 95 (18), 80 (5), 65 (5). IR ν
˜
= 1530, 1620, 3400 cm–1.
The acyclic urea 33 was obtained in two steps. 3-nitrophenyl isocya-
nate (2.67 g, 16.6 mmol) in acetone was added to 2-anisidine in
acetone under N2. The mixture was stirred for 3 hours and the
precipitate filtered, washed with diethylether and crystallised with
ethanol to give compound 32. This was deprotected with BBr3 at
–78° in dichloromethane under N2.
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Compound 32: 1970.5 mg, 42%, solid, m.p. 187–189 °C. H NMR
([D6]DMSO): δ = 3.88 (s, 3 H, OCH3), 6.85–7.10 (m, 3 H, Ar),
7.52–7.90 (m, 3 H, Ar), 8.13 (dd, J = 7.77, 1.39, 1 H, Ar), 8.31 (s,
1 H, NH), 8.58 (t, J = 2.21, 1 H, H-2), 9.91 (s, 1 H, NH) ppm.
MS: m/z (%) = 287 (60) [M+], 256 (10), 240 (10), 149 (28), 134 (20),
123 (75), 108 (100).
1
Compound 33: 560.0 mg, 47%, white solid, m.p. 215 °C. H NMR
([D6]DMSO): δ = 6.80–6.92 (m, 3 H, Ar), 7.51–8.12 (m, 4 H, Ar),
8.31 (s, 1 H, NH), 8.58 (t, J = 2.21, 1 H, H-2), 9.82 (s, 1 H, NH),
10.05 (br. s, 1 H, OH) ppm. MS: m/z (%) = 273 (18) [M+], 135 (30),
109 (100), 92 (8), 80 (15), 65 (9).
Synthesis of Carboxy Derivatives: Compounds 37, 39 and 40 were
prepared following the Goldberg general procedure as described
above.
Compound 37: 1252.0 mg, 59%, white solid, m.p. 140 °C. 1H NMR
(CDCl3): δ = 1.92 (br., 4 H, 2 CH2), 2.56 (br., 2 H, CH2CO), 3.61
(br., 2 H, CH2N), 7.18 (dd, J = 8.0, 0.7, 1 H, H-3), 7.48 (dt, J =
7.8, 0.7, 1 H, H-5), 7.54 (dt, J = 7.8, 0.7, 1 H, H-4), 7.98 (dd, J =
7.8, 0.7, 1 H, H-6) ppm. MS: m/z (%) 219 (60) [M+], 174 (65), 163
(100), 145 (60), 132 (70), 119 (30), 105 (20), 90 (20), 77 (40), 70
(15), 65 (20).
Compound 27: 649.6 mg, 81%, white solid, m.p. 167–168 °C. 1H
NMR (300 MHz, [D6]acetone): δ = 1.72 (br., 6 H, 3 CH2), 2.57 (m,
2 H, CH2CO), 3.62 (m, 2 H, CH2N), 6.88 (d, J = 8.0, 2 H, H-3
and H-5), 6.99 (d, J = 8.0, 2 H, H-2 and H-6) ppm. 13C NMR
([D6]acetone): δ = 24.3, 38.1, 53.6, 115.9 (two signals overlapping),
128.3 (two signals overlapping), 138.2, 156.1, 175.1 ppm. MS:
m/z (%) = 205 (100) [M+], 177 (5), 148 (18), 135 (20), 122 (90), 120
(18), 109 (3), 96 (5). HRMS (ESI): m/z = 228.09951 [M + Na]+.
Compound 39: 440.8 mg, 44%, white solid, m.p. 175–176 °C. 1H
NMR ([D6]DMSO): δ = 1.72 (br., 6 H, 3 CH2), 2.50 (br., 2 H,
CH2CO), 3.37 (br., 2 H, CH2N), 7.22 (dd, J = 8.0, 0.7, 1 H, H-3),
7.33 (dt, J = 7.7, 0.8, 1 H, H-5), 7.55 (dt, J = 7.7, 1.1, 1 H, H-4),
7.75 (dd, J = 7.5, 1.4, 1 H, H-6) ppm. HRMS (ESI): 256.09410 [M
+ Na]+.
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Compound 40: 148.9 mg, 45%, beige solid, m.p. 190 °C. H NMR
Synthesis of Ureidic Derivatives: The arylation of iodophenols was
performed under the same conditions described above for lactams
by using 2-imidazolidinone or tetrahydropyrimidin-2-one. The re-
sulting methyl ethers 28 and 29 were deprotected with BBr3 at –
78°C to give the title compounds.
([D6]acetone): δ = 1.81 (br., 6 H, 3 CH2), 2.62 (br., 2 H, CH2CO),
3.87 (br., 2 H, CH2N), 7.39–7.95 (m, 4 H, Ar) ppm. MS: m/z (%)
= 233 (100) [M+], 176 (70), 150 (90).
Compounds 34, 35 and 38 were synthesised following Scheme 4.
Compound 28: 640.0 mg, 29%, white solid, m.p. 158–161 °C. 1H
NMR (300 MHz, CDCl3): δ = 3.58 (t, J = 7.35, 2 H, CH2), 3.85
(s, 3 H, OCH3), 3.90 (t, J = 7.35, 2 H, CH2), 6.90–7.50 (m, 4 H,
General Procedure: A solution of acyl chloride in toluene was
added to a mixture of aminobenzoic acid (1 equiv) in pyridine at
0 °C. The mixture was stirred for 4–8 hours at 0 °C then allowed
to reach room temperature, filtered, evaporated to dryness, diluted
with water and extracted with ethyl acetate. The corresponding ha-
logenated amide was purified by flash chromatography.
Ar) ppm. MS: m/z (%) = 192 (100) [M+], 136 (10), 121 (18). IR ν
˜
= 1500, 1595, 1695, 3220 cm–1.
Compound 29: 30.0 mg, 11%, white solid, m.p. 174–178 °C. 1H
NMR (300 MHz, CDCl3): δ = 2.10 (m, 2 H, H-5), 2.60 (br. s, 1 H,
NH), 3.42 (m, 2 H, CH2) 3.83 (s, 3 H, OCH3), 6.90–7.34 (m, 4 H,
Ar) ppm. MS: m/z (%) = 206 (60) [M+], 175 (100), 147 (20), 136
(38), 120 (36), 106 (20), 92 (5), 77 (5), 65 (5).
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Compound 41: 1684.9 mg, 95%, colorless oil. H NMR (CDCl3): δ
= 2.21 (m, 2 H, CH2), 2.68 (t, J = 7.9, 2 H, CH2CO), 3.54 (t, J =
7.9, 2 H, CH2Br), 3.98 (s, 3 H, CO2CH3), 7.08 (dt, J = 7.8, 0.8, 1
H, H-5), 7.55 (dt, J = 7.8, 0.8, 1 H, H-4), 8.04 (dt, J = 7.8, 0.8, 1
H, H-3), 8.76 (dd, J = 7.8, 0.8, 1 H, H-6), 11.20 (br., 1 H, NH)
1
Compound 30: 430.7 mg, 32%, white solid, m.p. 105 °C. H NMR
(300 MHz, CDCl3): δ = 3.72 (m, 2 H, CH2), 4.04 (m, 2 H, CH2), ppm. MS: m/z (%) = 301 (25) [M + 1]+, 193 (35).
Eur. J. Org. Chem. 2006, 1656–1663
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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