Synthesis of 1-alkyltetrahydroisoquinolines

Article abstract of DOI:10.1007/s10600-013-0772-0

1-Alkyltetrahydroisoquinolines were prepared by a Bischler-Napieralski reaction starting from homoveratrylamine and monobasic acids. Their structures were confirmed by IR and NMR spectral data.

Full text of DOI:10.1007/s10600-013-0772-0

Chemistry of Natural Compounds, Vol. 49, No. 5, November, 2013 [Russian original No. 5, September–October, 2013]
SYNTHESIS OF 1-ALKYLTETRAHYDROISOQUINOLINES
1*
2
2
A. Sh. Saidov, M. G. Levkovich, and V. I. Vinogradova
UDC 547.945
1-Alkyltetrahydroisoquinolines were prepared by a Bischler–Napieralski reaction starting from
homoveratrylamine and monobasic acids. Their structures were confirmed by IR and NMR spectral data.
Keywords: Bischler–Napieralski reaction, 1-alkyltetrahydroisoquinolines, monobasic acids, homoveratrylamine.
Natural isoquinolines and their numerous derivatives exhibit high activity and are incorporated into many drugs [1,
2]. Derivatives of 3,4-dihydroisoquinoline garner the greatest number of publications on preparation methods, chemical
transformations, and pharmacological activity of simple isoquinolines [3–5].
Compounds combining rather long hydrocarbon chains with a cyclic tetrahydroisoquinoline moiety are of special
interest from a pharmacological viewpoint.
A simple synthetic scheme was used to synthesize the target products. This involved preparation of amides from
homoveratrylamine (1) and available fatty acids 2a–k (7:0, 9:0, 10:0, 12:0, 14:0, 16:0, 17:0, 18:0, 22:0, cis-18:1n9,
trans-18:1n9) with subsequent the Bischler–Napieralski cyclization and reduction of the 3,4-dihydroisoquinolines to
tetrahydroisoquinolines 4a–k.
H CO
3
O
CH OH
3
H C (CH )n CH CH
C
3
2
2
2
+
NH
2
tꢁ
OH
H CO
3
2a - k
1
5
8
4
1
2
H CO
3
ꢂ
H CO
3
3
ꢃ
NH
NH
1. POCl
2. NaBH
3
H CO
3
6
H CO
3
1'
CH
2'
CH
1'CH
2'CH
4
5
C
(CH )n CH
3
2
2
2
2
O
2
3a - k
(CH )n
2
CH
3
4a - k
a: n = 3; b: = 5; c: n= 6; d: n = 8; e: n = 10; f: n = 12; g: n = 13; h: n = 14
i: n = 18; j: n = 14, ꢄ cis; k: n = 14, ꢄ trans
9
9
Use in the first step of a previously prepared salt rather than a mixture of compounds enabled amides 3 to be obtained
–1
in high yields. IR spectra of amides 3a–k contained strong bands at 1638–1645 and 3010–3018 cm that corresponded to
stretching vibrations of CO and NH groups. PMR spectra of 3a–k showed resonances for protons of all structural fragments.
A feature of the PMR spectra was the fact that the 2-, 5-, and 6-protons of the aromatic ring formed a strongly coupled
ABC-system. Therefore, for example, proton H-5 in 3a–k appeared as a doublet at ꢀ 6.74 ppm with SSCC J = 8 Hz with
additional splitting because of the overlap of the H-2 and H-6 resonances. This was a second-order artifact. The nature of the
spectrum changed slightly upon heating to 50°C. The H-2 and H-6 resonances shifted whereas the H-5 resonance became
almost a regular doublet at 6.74 ppm with SSCC J = 8.6 Hz. Therefore, we present only chemical shifts for aromatic protons
of all amides 3a–k without indicating the resonance shape and SSCC.
The cyclization rate of amides 3a–k and high yields of isoquinolines 4a–k were practically independent of the alkyl
chain length. Only the reactions with oleic (cis-18:1, 2j) and elaidic (trans-18:1, 2k) acids gave very low product yields.
1) A. Navoi Samarkand State University, e-mail: a-saidov85@mail.ru; 2) S. Yu. Yunusov Institute of the Chemistry of
Plant Substances, Academy of Sciences of the Republic of Uzbekistan, Tashkent. Translated from Khimiya Prirodnykh
Soedinenii, No. 5, September–October, 2013, pp. 771–774. Original article submitted July 9, 2013.
©
0009-3130/13/4905-0897 2013 Springer Science+Business Media New York
897

The structures of the synthesized compounds were confirmed by IR and PMR spectral data. IR spectra of
4a–k lacked bands for amide carbonyl. PMR spectra exhibited a resonance for the H-1 proton at 4.35 ppm as a triplet with
J = 6–7 Hz. The nature of the resonances for aromatic H-5 and H-8 protons also changed. They appeared as singlets.
The facts that the melting points of the amides increased upon lengthening the chain whereas the melting points of the
tetrahydroisoquinoline hydrochlorides decreased and that the hydrochlorides of 4a–k dissolved readily in CHCl and poorly
3
in H O deserve attention.
2
EXPERIMENTAL
IR spectra were recorded in KBr pellets on an FTIR system 2000 instrument (PerkinElmer). PMR spectra were taken
in CDCl with HMDS internal standard on a Unity-400+ spectrometer (400 MHz, Varian). R values were determined on
3
f
LS 5/40 silica gel (Czech Rep.) using CHCl :MeOH (15:1, system 1; 10:1, system 2; 6:1, system 3; 4:1, system 4). Melting
3
points of all synthesized compounds were determined on a Boetius microstage.
General Method for Preparing Amides 3a–k. A mixture of homoveratrylamine (0.012 mol, using an excess of
amine) and monobasic acid (0.01 mol) in MeOH (5 mL) underwent spontaneous heating. The mixture was heated on an oil
bath for 2 h at 178°C, treated with CHCl (100 mL), and washed with HCl solution (3%), NaOH solution (2%), and H O until
3
2
neutral. The CHCl was evaporated. The residue was crystallized from Me CO or hexane. The resulting crystals were filtered
3
2
off.
N-(3,4-Dimethoxy-ꢃ-phenylethyl)heptanamide (3a). C H NO . Prepared from homoveratrylamine (1.84 g,
17 27
3
0.01 mol) and heptanoic acid (7:0, 1.32 g, 0.01 mol). Yield 84% (2.47 g), mp 55–57°C (hexane), R 0.54 (system 1).
f
–1
1
IR spectrum (ꢅ, cm ): 3310 (NH), 2933 (Ar-CH), 1645 (N-C=O). Í NMR spectrum (400 MHz, ÑDCl , ꢀ, ppm,
3
J/Hz): 0.81 (3Í, t, J = 7.3, ÑÍ ), 1.21 (6Í, br. s, 3ÑÍ ), 1.52 (2Í, m, Í-2ꢆ), 2.05 (2Í, t, J = 7.3, Í-1ꢆ), 2.70 (2Í, t, J = 7, Íꢂ),
3
2
3.43 (2Í, q, J = 7, Íꢃ), 3.795 (3Í, s, ÎÑÍ ), 3.801 (3Í, s, ÎÑÍ ), 5.45 (1Í, m, NH), 6.65 (1Í, Í-2), 6.67 (1Í, Í-6), 6.74
3
3
(1Í, Í-5).
N-(3,4-Dimethoxy-ꢃ-phenylethyl)nonanamide (3b). C H NO . Prepared from homoveratrylamine (2 g,
19 31
3
0.011 mol) and nonanoic acid (9:0, 1.32 g, 0.008 mol). Yield 92% (2.47 g), mp 69–71°C (hexane), R 0.6 (system 1).
f
–1
1
IR spectrum (ꢅ, cm ): 3310 (NH), 2925 (Ar-CH), 1639 (N-C=O). Í NMR spectrum (400 MHz, ÑDCl , ꢀ, ppm,
3
J/Hz): 0.81 (3Í, t, J = 7.5, ÑÍ ), 1.20 (10Í, br. s, 5ÑÍ ), 1.52 (2Í, m, Í-2ꢆ), 2.05 (2Í, t, J = 7.5, Í-1ꢆ), 2.70 (2Í, t, J = 7, Íꢂ),
3
2
3.43 (2Í, q, J = 7, Íꢃ), 3.799 (3Í, s, ÎÑÍ ), 3.805 (3Í, s, ÎÑÍ ), 5.37 (1Í, m, NH), 6.68 (1Í, Í-2), 6.70 (1Í, Í-6), 6.76
3
3
(1Í, Í-5).
N-(3,4-Dimethoxy-ꢃ-phenylethyl)decanamide (3c). C H NO . Prepared from homoveratrylamine (0.28 g,
20 33
3
1.5 mmol) and decanoic acid (10:0, 0.27 g, 1.5 mmol). Yield 83% (0.44 g), mp 81–82°C (Me CO), R 0.8 (system 1).
2
f
–1
1
IR spectrum (ꢅ, cm ): 3318 (NH), 2923 (Ar-CH), 1638 (N-C=O). Í NMR spectrum (400 MHz, ÑDCl , ꢀ, ppm, J/Ãö):
3
0.81 (3Í, t, J = 7.7, ÑÍ ), 1.19 (12Í, br. s, 6ÑÍ ), 1.53 (2Í, m, Í-2ꢆ), 2.05 (2Í, t, J = 7.7, Í-1ꢆ), 2.70 (2Í, t, J = 7, Íꢂ), 3.43
3
2
(2Í, q, J = 7, Íꢃ), 3.80 (3Í, s, ÎÑÍ ), 3.81 (3Í, s, ÎÑÍ ), 5.36 (1Í, m, NH), 6.65 (1Í, Í-2), 6.70 (1Í, Í-6), 6.76 (1Í,
3
3
Í-5).
N-(3,4-Dimethoxy-ꢃ-phenylethyl)dodecanamide (3d). C H NO . Prepared from homoveratrylamine (0.2 g,
22 37
3
1.1 mmol) and dodecanoic acid (12:0, 0.18 g, 0.9 mmol). Yield 88% (0.29 g), mp 88–90°C (Me CO), R 0.88 (system 1).
2
f
–1
1
IR spectrum (ꢅ, cm ): 3318 (NH), 2917 (Ar-CH), 1638 (N-C=O). Í NMR spectrum (400 MHz, ÑDCl , ꢀ, ppm,
3
J/Hz): 0.81 (3Í, t, J = 7.7, ÑÍ ), 1.18 (16Í, br. s, 8ÑÍ ), 1.51 (2Í, m, Í-2ꢆ), 2.05 (2Í, t, J = 7.7, Í-1ꢆ), 2.70 (2Í, t, J = 7, Íꢂ),
3
2
3.43 (2Í, q, J = 7, Íꢃ), 3.80 (3Í, s, ÎÑÍ ), 3.81 (3Í, s, ÎÑÍ ), 5.33 (1Í, m, NH), 6.65 (1Í, Í-2), 6.70 (1Í, Í-6), 6.76 (1Í,
3
3
Í-5).
N-(3,4-Dimethoxy-ꢃ-phenylethyl)tetradecanamide (3e). C H NO . Prepared from homoveratrylamine (0.16 g,
24 41
3
0.9 mmol) and tetradecanoic acid (14:0, 0.14 g, 0.6 mmol). Yield 71% (0.17 g), mp 94–95°C (Me CO), R 0.9 (system 1).
2
f
–1
1
IR spectrum (ꢅ, cm ): 3318 (NH), 2917 (Ar-CH), 1638 (N-C=O). Í NMR spectrum (400 MHz, ÑDCl , ꢀ, ppm,
3
J/Hz): 0.81 (3Í, t, J = 7.5, ÑÍ ), 1.18 (20Í, br. s, 10ÑÍ ), 1.5 (2Í, m, H-2ꢆ), 2.05 (2Í, t, J = 7.5, H-1ꢆ), 2.70 (2Í, t, J = 7, Íꢂ),
3
2
3.44 (2Í, q, J = 7, Íꢃ), 3.80 (3Í, s, ÎÑÍ ), 3.81 (3Í, s, ÎÑÍ ), 5.32 (1Í, m, NH), 6.65 (1Í, Í-2), 6.70 (1Í, Í-6), 6.76 (1Í,
3
3
Í-5).
N-(3,4-Dimethoxy-ꢃ-phenylethyl)hexadecanamide (3f). C H NO . Prepared from homoveratrylamine (0.6 g,
26 45
3
3.3 mmol) and hexadecanoic acid (16:0, 0.75 g, 3 mmol). Yield 84.5% (1.04 g), mp 102–103°C (Me CO), R 0.9 (system 2).
2
f
898

–1
1
IR spectrum (ꢅ, cm ): 3318 (NH), 2917 (Ar-CH), 1638 (N-C=O). Í NMR spectrum (400 MHz, ÑDCl , ꢀ, ppm,
3
J/Hz): 0.81 (3Í, t, J = 7.7, ÑÍ ), 1.18 (24Í, br. s, 12ÑÍ ), 1.53 (2Í, m, Í-2ꢆ), 2.05 (2Í, t, J = 7.7, Í-1ꢆ), 2.70 (2Í, t, J = 7,
3
2
Íꢂ), 3.43 (2Í, q, J = 7, Íꢃ), 3.80 (3Í, s, ÎÑÍ ), 3.81 (3Í, s, ÎÑÍ ), 5.35 (1Í, m, NH), 6.65 (1Í, Í-2), 6.70 (1Í, Í-6), 6.76
3
3
(1Í, Í-5).
N-(3,4-Dimethoxy-ꢃ-phenylethyl)heptadecanamide (3g). C H NO . Prepared from homoveratrylamine (1.4 g,
27 47
3
7.7 mmol) and heptadecanoic acid (17:0, 2 g, 7.4 mmol). Yield 82% (2.62 g), mp 99–101°C (Me CO), R 0.8 (system 2).
2
f
–1
1
IR spectrum (ꢅ, cm ): 3312 (NH), 2920 (Ar-CH), 1639 (N-C=O). Í NMR spectrum (400 MHz, ÑDCl , ꢀ, ppm,
3
J/Hz): 0.81 (3Í, t, J = 7.2, ÑÍ ), 1.18 (26Í, br. s, 13ÑÍ ), 1.52 (2Í, m, H-2ꢆ), 2.05 (2Í, t, J = 7.2, H-1ꢆ), 2.70 (2Í, t, J = 7,
3
2
Íꢂ), 3.43 (2Í, q, J = 7, Íꢃ), 3.80 (3Í, s, ÎÑÍ ), 3.81 (3Í, s, ÎÑÍ ), 5.32 (1Í, m, NH), 6.65 (1Í, Í-2), 6.70 (1Í, Í-6), 6.76
3
3
(1Í, Í-5).
N-(3,4-Dimethoxy-ꢃ-phenylethyl)octadecanamide (3h). C H NO . Prepared from homoveratrylamine (0.4 g,
28 49
3
2.2 mmol) and octadecanoic acid (18:0, 0.61 g, 2 mmol). Yield 82% (0.79 g), mp 103–104°C (Me CO), R 0.88 (system 2).
2
f
–1
1
IR spectrum (ꢅ, cm ): 3309 (NH), 2920 (Ar-CH), 1639 (N-C=O). Í NMR spectrum (400 MHz, ÑDCl , ꢀ, ppm,
3
J/Hz): 0.81 (3Í, t, J = 7.7, ÑÍ ), 1.18 (28Í, br. s, 14ÑÍ ), 1.55 (2Í, m, Í-2ꢆ), 2.05 (2Í, t, J = 7.7, Í-1ꢆ), 2.70 (2Í, t, J = 6.8,
3
2
Íꢂ), 3.43 (2Í, q, J = 6.1, Íꢃ), 3.80 (3Í, s, ÎÑÍ ), 3.81 (3Í, s, ÎÑÍ ), 5.35 (1Í, m, NH), 6.65 (1Í, Í-2), 6.70 (1Í, Í-6),
3
3
6.76 (1Í, Í-5).
N-(3,4-Dimethoxy-ꢃ-phenylethyl)docosanamide (3i). C H NO . Prepared from homoveratrylamine (0.5 g,
32 53
3
2.8 mmol) and docosanoic acid (22:0, 0.84 g, 2.6 mmol). Yield 83% (1.03 g), mp 105–107°C (Me CO), R 0.9 (system 2).
2
f
–1
1
IR spectrum (ꢅ, cm ): 3313 (NH), 2920 (Ar-CH), 1639 (N-C=O). Í NMR spectrum (400 MHz, ÑDCl , ꢀ, ppm,
3
J/Hz): 0.81 (3Í, t, J = 7.7, ÑÍ ), 1.18 (36Í, br. s, 18ÑÍ ), 1.52 (2Í, m, Í-2ꢆ), 2.05 (2Í, t, J = 7.7, Í-1ꢆ), 2.70 (2Í, t, J = 7,
3
2
Íꢂ), 3.43 (2Í, q, J = 7, Íꢃ), 3.80 (3Í, s, ÎÑÍ ), 3.81 (3Í, s, ÎÑÍ ), 5.35 (1Í, m, NH), 6.65 (1Í, Í-2), 6.70 (1Í, Í-6), 6.76
3
3
(1Í, Í-5).
N-(3,4-Dimethoxy-ꢃ-phenylethyl)octadecen-9-amide (cis) (3j). C H NO . Prepared from homoveratrylamine
28 47
3
(1 g, 5.5 mmol) and oleic acid (18:1n9, 1.5 g, 5.3 mmol). Yield 63% (1.5 g), mp 105–107°C (Me CO), R 0.83 (system 2).
2
f
–1
1
IR spectrum (ꢅ, cm ): 3317 (NH), 2920 (Ar-CH), 1639 (N-C=O). Í NMR spectrum (400 MHz, ÑDCl , ꢀ, ppm,
3
J/Hz): 0.82 (3Í, t, J = 7, ÑÍ ), 1.20 (22Í, br. s, 11ÑÍ ), 1.52 (3Í, m, H-7ꢆ, 10ꢆ), 1.98 (1Í), 2.04 (2Í, t, J = 7.6, H-1ꢆ), 2.70
3
2
(2Í, t, J = 7, Íꢂ), 3.43 (2Í, q, J = 7, Íꢃ), 3.79 (3Í, s, ÎÑÍ ), 3.80 (3Í, s, ÎÑÍ ), 5.28 (2Í, m, ÑH=ÑÍ); 6.66 (1Í, Í-2), 6.67
3
3
(1Í, Í-6), 6.75 (1Í, Í-5).
N-(3,4-Dimethoxy-ꢃ-phenylethyl)octadecen-9-amide (trans) (3k). C H NO . Prepared from homoveratrylamine
28 47
3
(0.2 g, 1.1 mmol) and elaidic acid (18:1n9, 0.27 g, 1 mmol). Yield 70% (0.3 g), mp 105–107°C (Me CO), R 0.73 (system 2).
2
f
–1
1
IR spectrum (ꢅ, cm ): 3318 (NH), 2920 (Ar-CH), 1638 (N-C=O). Í NMR spectrum (400 MHz, ÑDCl , ꢀ, ppm,
3
J/Hz): 0.81 (3Í, t, J = 7, ÑÍ ), 1.20 (20Í, br. s, 10ÑÍ ), 1.50 (2Í, m, H-2ꢆ), 1.88 (2Í, t, J = 7.2, H-7, 10), 2.05 (2Í, t, J = 7,
3
2
Í-1ꢆ), 2.70 (2Í, t, J = 7, Íꢂ), 3.43 (2Í, q, J = 7, Íꢃ), 3.80 (3Í, s, ÎÑÍ ), 3.81 (3Í, s, ÎÑÍ ), 5.31 (2Í, m, ÑH), 6.65 (1Í,
3
3
Í-2), 6.67 (1Í, Í-6), 6.75 (1Í, Í-5).
General Method for Preparing Tetrahydroisoquinolines 4a–k. A mixture of amide of monobasic acid (6 mmol),
anhydrous benzene (30 mL), and POCl (12 mmol) was refluxed for 1 h. The course of the reaction was monitored by TLC.
3
The benzene and POCl were distilled off. The residue was dissolved in MeOH (30 mL) and treated in portions at 0–5°C with
3
NaBH (0.02 mol). The MeOH was distilled off. The residue was dissolved in H O and extracted with CHCl . The CHCl
4
2
3
3
was removed. Isoquinolines 4a–k were crystallized from Me CO.
2
1-Hexyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (4a). C H NO . Prepared from amide 3a (1 g, 3.4 mmol)
17 27
2
and POCl (0.7 mL). Yield 74% (0.7 g), mp of hydrochloride 188–191°C (Me CO), R 0.6 (system 4).
3
2
f
–1
1
IR spectrum (ꢅ, cm ): 3450, 2930, 1611, 1519, 1450, 1264. Í NMR spectrum (400 MHz, ÑD OD, ꢀ, ppm, J/Hz): 0.86
3
(3Í, m, J = 6, ÑÍ ), 1.30 (6Í, d, J = 6, 3ÑÍ ), 1.38 and 1.44 (each 1Í, m, ÑÍ ), 1.84 and 2.05 (each 1Í, m, H-1ꢆ), 2.96 (2Í, m,
3
2
2
Í-4), 3.47 (2Í, q, J = 6, Í-3), 3.76 (6Í, s, 2ÎÑÍ ), 4,40 (1Í, m, H-1), 6.74 (2Í, s, Í-5, 8).
3
1-Octyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (4b). C H NO . Prepared from amide 3b (1.3 g, 4 mmol)
19 31
2
and POCl (0.8 mL). Yield 71% (0.87 g), mp of hydrochloride 177–180°C (Me CO), R 0.6 (system 4).
3
2
f
–1
1
IR spectrum (ꢅ, cm ): 3611, 2928, 1611, 1519, 1460, 1264. Í NMR spectrum (400 MHz, ÑDCl , ꢀ, ppm, J/Hz):
3
0.81 (3Í, m, J = 7.0, ÑÍ ), 1.20 (10Í, br. s, 5ÑÍ ), 1.57 (2Í, q, J = 7.4, H-1ꢆ, 2ꢆ), 2.98 and 3.09 (each 1Í, t, J = 6, Í-4), 3.26
3
2
and 3.50 (each 1Í, q, J = 6.4, Í-3), 3.78 (3Í, s, ÎÑÍ ), 3.79 (3Í, s, ÎÑÍ ), 4.35 (1Í, t, J = 6.6, H-1), 6.50 (1Í, s, Í-8), 6.53 (1Í, s,
3
3
Í-5).
899

1-Nonyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (4c). C H NO . Prepared from amide 3c (0.26 g,
20 33
2
0.8 mmol) and POCl (0.25 mL). Yield 80% (0.2 g), mp of hydrochloride 173–176°C (Me CO), R 0.55 (system 3).
3
2
f
–1
1
IR spectrum (ꢅ, cm ): 3749, 2926, 1611, 1519, 1449, 1265. Í NMR spectrum (400 MHz, ÑDCl , ꢀ, ppm, J/Hz):
3
0.81 (3Í, t, J = 7.0, ÑÍ ), 1.20 (12Í, br. s, 6ÑÍ ), 1.57 (4Í, q, J = 8, H-1ꢆ, 2ꢆ), 2.99–3.10 (each 1Í, t, J = 6, Í-4), 3.26 (1Í, q,
3
2
J = 6, Í-3à), 3.50 (1Í, q, J = 6, Í-3b), 3.78 (3Í, s, ÎÑÍ ), 3.79 (3Í, s, ÎÑÍ ), 4.35 (1Í, t, J = 6, H-1), 6.50 (1Í, s, Í-8), 6.53 (1Í,
3
3
s, Í-5).
1-Undecyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (4d). C H NO . Prepared from amide 3d (0.14 g,
22 37
2
0.4 mmol) and POCl (0.10 mL). Yield 77% (0.1 g), mp of hydrochloride 165–168°C (Me CO), R 0.62 (system 3).
3
2
f
–1
1
IR spectrum (ꢅ, cm ): 3450, 2925, 1612, 1519, 1460, 1263. Í NMR spectrum (400 MHz, ÑDCl , ꢀ, ppm, J/Hz):
3
0.81 (3Í, t, J = 7, ÑÍ ), 1.19 (16Í, br. s, 8ÑÍ ), 1.56 (4Í, q, J = 7.4, H-1ꢆ, 2ꢆ), 2.98 and 3.10 (each 1Í, t, J = 6, Í-4), 3.26 (1Í, q,
3
2
J = 6, Í-3à), 3.50 (1Í, q, J = 6, Í-3b), 3.78 (3Í, s, ÎÑÍ ), 3.79 (3Í, s, ÎÑÍ ), 4.35 (1Í, t, J = 6, H-1), 6.50 (1Í, s, Í-85), 6.53
3
3
(1Í, s, Í-5).
1-Tridecyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (4e). C H NO . Prepared from amide 3e (0.15 g,
24 41
2
0.4 mmol) and POCl (0.10 mL). Yield 71% (0.1 g), mp of hydrochloride 155–158°C (Me CO), R 0.44 (system 3).
3
2
f
–1
1
IR spectrum (ꢅ, cm ): 3608, 2923, 1612, 1519, 1460, 1264. Í NMR spectrum (400 MHz, ÑDCl , ꢀ, ppm, J/Hz):
3
0.81 (3Í, t, J = 7, ÑÍ ), 1.19 (20Í, br. s, 10ÑÍ ), 1.57 (4Í, q, J = 7.4, H-1ꢆ, 2ꢆ), 2.98 and 3.09 (each 1Í, t, J = 6.4, Í-4), 3.26 (1Í,
3
2
q, J = 6.6, Í-3à), 3.50 (1Í, q, J = 6.6, Í-3b), 3.78 (3Í, s, ÎÑÍ ), 3.79 (3Í, s, ÎÑÍ ), 4.35 (1Í, t, J = 6, H-1), 6.50 (1Í, s, Í-8), 6.53
3
3
(1Í, s, Í-5).
1-Pentadecyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (4f). C H NO . Prepared from amide 3f (0.9 g,
26 45
2
0.002 mol) and POCl (0.4 mL). Yield 88% (0.76 g), mp of hydrochloride 155–158°C (Me CO), R 0.62 (system 4).
3
2
f
–1
1
IR spectrum (ꢅ, cm ): 3608, 2921, 1612, 1519, 1469, 1264. Í NMR spectrum (400 MHz, ÑDCl , ꢀ, ppm, J/Hz):
3
0.80 (3Í, t, J = 7.0, ÑÍ ), 1.16 (26Í, br. s, 13ÑÍ ), 1.57 (2Í, m, H-2ꢆ), 2.34 (1Í, m, Í-4à), 2.58 (2Í, br. s, Í-1ꢆ), 2.77 (1Í,
3
2
m, Í-4b), 3.04 (1Í, m, Í-3à), 3.48 (1Í, q, J = 6.6, Í-3b), 3.73 (6Í, s, 2ÎÑÍ ), 4.35 (1Í, q, J = 5.6, H-1), 6.43 (1Í, s,
3
Í-8), 6.47 (1Í, s, Í-5).
1-Hexadecyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (4g). C H NO . Prepared from amide 3g (1 g,
27 47
2
2.3 mmol) and POCl (0.5 mL). Yield 90% (0.86 g), mp of hydrochloride 154–156°C (Me CO), R 0.42 (system 3).
3
2
f
–1
1
IR spectrum (ꢅ, cm ): 3607, 2923, 1611, 1519, 1462, 1264. Í NMR spectrum (400 MHz, ÑDCl , ꢀ, ppm, J/Hz):
3
0.81 (3Í, t, J = 6.7, ÑÍ ), 1.19 (26Í, br. s, 13ÑÍ ), 1.44 (2Í, q, J = 8, H-2ꢆ), 1.92 (2Í, q, J = 8.5, H-1ꢆ), 2.65 and 2.73
3
2
(each 1Í, t, J = 6.4, Í-4), 2.95 (1Í, q, J = 6, Í-3à), 3.21 (1Í, q, J = 6, Í-3b), 3.78 (6Í, s, ÎÑÍ ), 3.92 (1Í, q, J = 6, H-1), 6.50
3
(1Í, s, Í-8), 6.54 (1Í, s, Í-5).
1-Heptadecyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (4h). C H NO . Prepared from amide 3h (0.75 g,
28 49
2
1.7 mmol) and POCl (0.4 mL). Yield 70% (0.5 g), mp of hydrochloride 143–146°C (Me CO), R 0.57 (system 3).
3
2
f
–1
1
IR spectrum (ꢅ, cm ): 3450, 2920, 1612, 1519, 1470, 1264. Í NMR spectrum (400 MHz, ÑDCl , ꢀ, ppm, J/Hz):
3
0.81 (3Í, t, J = 7, ÑÍ ), 1.18 (30Í, br. s, 15ÑÍ ), 1.57 (4Í, q, J = 7.5, H-1ꢆ, 2ꢆ), 2.99 (1Í, t, J = 6.17, Í-4à), 3.10 (1Í, t,
3
2
J = 6.17, Í-4b), 3.33 (1Í, q, J = 6, 12.5, Í-3à), 3.50 (1Í, q, J = 6, 12.5, Í-3b), 3.78 (3Í, s, ÎÑÍ ), 3.79 (3Í, s, ÎÑÍ ), 4.35
3
3
(1Í, t, J = 6.4, H-1), 6.50 (1Í, s, Í-8), 6.53 (1Í, s, Í-5).
1-Heneicosyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (4i). C H NO . Prepared from amide 3i (0.9 g,
32 57
2
1.8 mmol) and POCl (0.4 mL). Yield 92% (0.8 g), mp of hydrochloride 143–146°C (Me CO), R 0.57 (system 3).
3
2
f
–1
1
IR spectrum (ꢅ, cm ): 3342, 2916, 1610, 1518, 1451, 1257. Í NMR spectrum (400 MHz, ÑDCl , ꢀ, ppm, J/Hz):
3
0.81 (3Í, t, J = 6.7, ÑÍ ), 1.19 (38Í, br. s, 19ÑÍ ), 1.57 (4Í, m, H-1ꢆ, 2ꢆ), 2.60 and 2.65 (each 1Í, t, J = 6, Í-4), 2.90 (1Í, q,
3
2
J = 6, Í-3à), 3.15 (1Í, q, J = 7.6, Í-3b), 3.78 (3Í, s, ÎÑÍ ), 3.79 (3Í, s, ÎÑÍ ), 3.82 (1Í, m, H-1), 6.50 (1Í, s, Í-8), 6.55
3
3
(1Í, s, Í-5).
1-(Heptadecen-8-yl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (cis) (4j). C H NO . Prepared from amide
28 47
2
3j (0.5 g, 1.1 mmol) and POCl (0.25 mL). Yield 62% (0.3 g), mp of hydrochloride 146–149°C (Me CO), R 0.4 (system 3).
3
2
f
–1
1
IR spectrum (ꢅ, cm ): 3424, 2922, 1612, 1519, 1460, 1264. Í NMR spectrum (400 MHz, ÑDCl , ꢀ, ppm, J/Hz):
3
0.80 (3Í, t, J = 7, ÑÍ ), 1.18 (24Í, br. s, 12ÑÍ ), 1.57 (2Í, q, J = 6.8, H-1ꢆ), 1.99 (2Í, q, J = 7, H-7ꢆ), 2.99 (1Í, t, J = 6.5,
3
2
Í-4à), 3.09 (1Í, t, J = 6.5, Í-4b), 3.26 (1Í, q, J = 6.4, Í-3à), 3.50 (1Í, q, J = 6.4, Í-3b), 3.78 (3Í, s, ÎÑÍ ), 3.79 (3Í, s,
3
ÎÑÍ ), 4.35 (1Í, t, J = 6, ÑH-1), 5.23 (1Í, m, ÑÍ=ÑÍ), 6.49 (1Í, s, Í-8), 6.52 (1Í, s, Í-5).
3
1-(Heptadecen-8-yl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (trans) (4k). C H NO . Prepared from amide
28 47
2
3k (0.15 g, 0.34 mmol) and POCl (0.1 mL). Yield 71% (0.1 g), mp of hydrochloride 148–151°C (Me CO), R 0.4 (system 3).
3
2
f
900

–1
1
IR spectrum (ꢅ, cm ): 3424, 2922, 1611, 1519, 1469, 1264. Í NMR spectrum (400 MHz, ÑDCl , ꢀ, ppm, J/Hz):
3
0.81 (3Í, t, J = 7, ÑÍ ), 1.19 (22Í, br. s, 11ÑÍ ), 1.57 (2Í, q, J = 7.4, H-1ꢆ), 1.90 (2Í, q, J = 7, H-7ꢆ), 2.04 (2Í, t, J = 7, H-10ꢆ),
3
2
2.99 (1Í, t, J = 6, Í-4à), 3.12 (1Í, t, J = 6, Í-4b), 3.26 (1Í, q, J = 6.6, Í-3à), 3.50 (1Í, q, J = 6.6, Í-3b), 3.78 (3Í, s, ÎÑÍ ),
3
3.79 (3Í, s, ÎÑÍ ), 4.34 (1Í, t, J = 6.4, H-1), 5.33 (2Í, q, J = 2, ÑÍ=ÑÍ), 6.50 (1Í, s, Í-8), 6.53 (1Í, s, Í-5).
3
REFERENCES
1.
2.
Yu. V. Shklyaev, B. Ya. Syropyatov, and V. S. Shklyaev, Bashkir. Khim. Zh., 4 (4), 19 (1997).
A. G. Mikhailovskii, B. Ya. Syropyatov, A. V. Dolzhenko, and V. S. Shklyaev, Nitrogeneous Heterocycles and Alkaloids
[in Russian], Vol. 1, V. G. Kartsev and G. A. Tolstikov (eds.), Iridium-Press, Moscow, 2001, pp. 435-439.
V. V. Khalturina, Yu. V. Shklyaev, R. R. Makhmudov, and A. N. Maslivets, Khim.-farm. Zh., 44 (9), 14 (2010).
M. Yu. Dormidontov, B. Ya. Syropyatov, R. Z. Dautova, B. B. Aleksandrov, V. S. Shklyaev, M. I. Vakhrin, and
A. G. Mikhailovskii, Khim.-farm. Zh., 22 (12), 22 (1990).
3.
4.
5.
A. G. Mikhailovskii, Yu. N. Bubnov, B. Ya. Syropyatov, A. V. Doldzhenko, and Yu. P. Timofeeva, Khim.-farm. Zh.,
33 (3), 15 (1999).
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