Synthesis of bis-tetrahydroisoquinolines based on homoveratrylamine and a series of dibasic acids. 1.

Article abstract of DOI:10.1007/s10600-013-0586-0

Bis-tetrahydroisoquinolines were prepared starting from homoveratrylamine and dicarboxylic acids using the Bischler-Napieralski reaction. Their structures were confirmed using IR and NMR spectral data.

Full text of DOI:10.1007/s10600-013-0586-0

Chemistry of Natural Compounds, Vol. 49, No. 2, May, 2013 [Russian original No. 2, March–April, 2013]
SYNTHESIS OF BIS-TETRAHYDROISOQUINOLINES
BASED ON HOMOVERATRYLAMINE AND
A SERIES OF DIBASIC ACIDS. 1.
A. Sh. Saidov,1* M. Alimova, M. G. Levkovich,
and V. I. Vinogradova
1
2
UDC 547.945
2
Bis-tetrahydroisoquinolines were prepared starting from homoveratrylamine and dicarboxylic acids using
the Bischler–Napieralski reaction. Their structures were confirmed using IR and NMR spectral data.
Keywords: Bischler–Napieralski reaction, bis-tetrahydroisoquinolines, dibasic acids, homoveratrylamine.
Structural studies of new isoquinoline alkaloids [1] and the search for biologically active analogs or their derivatives
2, 3] have influenced considerably the development of the chemistry of heterocyclic compounds. Isoquinoline derivatives
[
include a multitude of highly effective biologically active compounds and drugs [4–6]. One of the key issues in the creation
of new types of biologically active compounds is the development of convenient synthetic methods. The overwhelming
majority of isoquinolines are prepared using the well-known reactions Pomeranz–Fritsch, Bischler–Napieralski, Pictet–Spengler
[
7], and others. The structure of the target product and the availability of starting materials determine which reaction is used.
We studied the reaction of homoveratrylamine (1) with dicarboxylic acids 2a–d in order to prepare new derivatives
and to study their biological activity. Amides 3a–d were obtained readily upon heating the salt to 175°C for 1–2 h. The second
step used POCl as a condensing agent [7]. Reduction by NaBH of 3,4-dihydroisoquinolines 4a–d produced target isoquinolines
3
4
5
a–d.
2
ꢁ
ꢁ
2
OCH
OCH
H
H
3
3
CO
CO
H
H
3
3
CO
CO
3
3
ꢀ
t
ꢂ
ꢂ
a
+ HOOC(CH
2
)nCOOH
NH
NH
2
HN
1'
C
5
5
1
2a - d
(CH
2
)n
C
O
O
3
a - d
H
3
3
CO
CO
H
H
3
3
CO
CO
3
7
N
1
NH
H
b
(
CH
2
)n
2
(CH )n
OCH
OCH
3
7
OCH
OCH
3
N
HN
1
4
3
3
4
a - d
a: n = 4; b: n = 5; c: n = 7; d: n = 8
a. POCl , C H ; b. NaBH , CH OH
5a - d
3
6
6
4
3
Products 3a–d and 5a–d were characterized using IR and NMR spectral data. Thus, PMR spectra of 5a–d, in contrast
with those of 3a–d, contained resonances for H-1 protons at 3.8–4.0 ppm and resonances for aromatic protons H-5 and H-8 as
two singlets at 6.49–6.54 ppm. However, resonances for aromatic protons in spectra of amides 3a–d were found at 6.65 (2H,
d, J = 2, H-2), 6.66 (2H, dd, J = 8.5–8.8, 2, H-6), and 6.74 (2H, d, J = 8.5–8.8, H-5).
1
) A. Navoi Samarkand State University, Republic of Uzbekistan, e-mail: a-saidov@samdu.uz; 2) S. Yu. Yunusov
Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan, Tashkent, fax: (99871)
20 64 75. Translated from Khimiya Prirodnykh Soedinenii, No. 2, March–April, 2013, pp. 257–258. Original article submitted
December 25, 2012.
1
302
0009-3130/13/4902-0302 ©2013 Springer Science+Business Media New York

EXPERIMENTAL
IR spectra were recorded in KBr pellets on an FTIR System 2000 instrument (Perkin–Elmer). PMR spectra were
recorded on a Unity-400+ spectrometer (400 MHz, CDCl solvent, HMDS internal standard). The R values were determined
3
f
on LS 5/40 silica gel plates (Czechoslovakia) using CHCl :MeOH (system 1, 12:1; 2, 10:1; 3, 8:1). Melting points of all
3
synthesized compounds were determined on a Boetius microstage.
General Method for Preparing Diamides 3a–d. A mixture of homoveratrylamine (1, 0.02 mol) and dibasic acid
(
0.01 mol) was dissolved in MeOH (10 mL). The mixture underwent self-heating. The MeOH was distilled off. The resulting
salt was heated on an oil bath for 1–2 h at 175–178°C, dissolved in CHCl (100 mL), and washed with HCl solution (3%),
3
NaOH solution (2%), and H O until neutral. The CHCl was distilled off. The solid was crystallized from Me CO. The
2
3
2
resulting crystals were filtered off.
N,Nꢃ-(3,4-Dimethoxy-ꢂ-phenylethyl)-adipoyl diamide (3a), C H N O , was prepared from 1 (4.6 g, 0.03 mol)
2
6 36 2 6
–
1
and adipic acid (1.95 g, 0.013 mol). Yield 77% (4.64 g), mp 173–175°C (Me CO), R 0.4 (system 1). IR spectrum (ꢄ, cm ):
2
f
3
313 (NH), 1634 (CO). PMR spectrum (400 MHz, CDCl , ꢅ, ppm, J/Hz): 1.54 (4H, m, H-3ꢃ, 4ꢃ), 2.07 (4H, m, H-2ꢃ, 5ꢃ), 2.69
3
(
(
4H, t, J = 6.95, H-ꢁ), 3.42 (4H, q, J = 7.14, H-ꢂ), 3.791 (6H, s, OCH ), 3.797 (6H, s, OCH ), 5.66 (2H, t, J = 5.6, NH), 6.65
2H, d, J = 1.9, H-2), 6.66 (2H, dd, J = 8.7, 1.9, H-6), 6.74 (2H, d, J = 8.7, H-5).
3
3
N,Nꢃ-(3,4-Dimethoxy-ꢂ-phenylethyl)-pimeloyl diamide (3b), C H N O , was prepared from 1 (1.87 g, 0.01
2
7 38 2 6
mol) and pimelic acid (0.9 g, 0.005 mol). Yield 62.4% (1.56 g), mp 138–141°C (Me CO), R 0.75 (system 2). IR spectrum
2
f
–
1
(
ꢄ, cm ): 3307 (NH), 1643 (CO). PMR spectrum (400 MHz, CDCl , ꢅ, ppm, J/Hz): 1.20 (2H, m, H-4ꢃ), 1.52 (4H, m, H-3ꢃ, 5ꢃ),
3
2
5
.04 (4H, t, J = 7.5, H-2ꢃ, 6ꢃ), 2.70 (4H, t, J = 7.0, H-ꢁ), 3.43 (4H, q, J = 7.0, H-ꢂ), 3.793 (6H, s, OCH ), 3.796 (6H, s, OCH ),
.51 (2H, br.t, J = 5.6, NH), 6.65 (2H, d, J = 2, H-2), 6.66 (2H, dd, J = 2, 8.8, H-6), 6.74 (2H, d, J = 8.8, H-5).
3
3
N,Nꢃ-(3,4-Dimethoxy-ꢂ-phenylethyl)-azelaoyl diamide (3c), C H N O , was prepared from 1 (1.58 g,
2
9
42
2 6
0
(
.009 mol) and azelaic acid (0.9 g, 0.005 mol). Yield 66% (1.48 g), mp 141–145°C (Me CO), R 0.74 (system 2). IR spectrum
ꢄ, cm ): 3306 (NH), 1642 (CO). PMR spectrum (400 MHz, CDCl , ꢅ, ppm, J/Hz): 1.20 (6H, s, H-4ꢃ, 5ꢃ, 6ꢃ), 1.51 (4H, t,
2 f
–
1
3
J = 6.7, H-3ꢃ, 7ꢃ), 2.04 (4H, t, J = 7.5, H-2ꢃ, 8ꢃ), 2.69 (4H, t, J = 6.96, H-ꢁ), 3.43 (4H, q, J = 6.4, H-ꢂ), 3.79 (12H, s, OCH ), 5.52
3
(
2H, t, NH), 6.65 (2H, s, H-2), 6.64 (2H, d, J = 2, 8.5, H-6), 6.74 (2H, d, J = 8.5, H-5).
N,Nꢃ-(3,4-Dimethoxy-ꢂ-phenylethyl)-sebacoyl diamide (3d), C H N O , was prepared from 1 (1.59 g, 0.009
3
0 44 2 6
mol) and sebacic acid (0.98 g, 0.004 mol). Yield 65% (1.5 g), mp 152–156°C (Me CO), R 0.75 (system 2). IR spectrum
2
f
–
1
(
ꢄ, cm ): 3310 (NH), 1639 (CO). PMR spectrum (400 MHz, CDCl , ꢅ, ppm, J/Hz): 1.182 (8H, s, H-4ꢃ, 5ꢃ, 6ꢃ, 7ꢃ), 1.503 (4H,
3
t, J = 6.9, H-3ꢃ, 8ꢃ), 2.04 (4H, t, J = 7.4, H-2ꢃ, 9ꢃ), 2.68 (4H, t, J = 6.9, H-ꢁ), 3.41 (4H, q, J = 6.8, H-ꢂ), 3.78 (12H, s, OCH ), 5.59
3
(
2H, t, J = 5.5, NH), 6.64 (2H, s, H-2), 6.65 (2H, d, J = 8.5, H-6), 6.73 (2H, d, J = 8.5, H-5).
General Method for Preparing bis-Tetrahydroisoquinolines 5a–d. A mixture of dibasic acid amide (0.006 mol),
anhydrous benzene (30 mL), and POCl (0.05 mol) was refluxed for 2 h. The course of the reaction was monitored by TLC.
3
Benzene and POCl were distilled off. The residue was dissolved in MeOH (30 mL). The resulting solution was cooled to
3
0
–5°C and treated in portions with NaBH (0.02 mol). The MeOH was distilled off. The residue was dissolved in H O and
4
2
extracted with CHCl . The CHCl was removed. The solid was crystallized from Me CO.
3
3
2
1
,4-bis-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)butane (5a), C H N O , was prepared from 3a
3 g, 0.006 mol) and POCl (7 mL). Yield 76% (2.09 g), mp 112–116°C (Me CO), R 0.1 (system 3). IR spectrum (ꢄ, cm ):
26 36 2 4
–
1
(
3
2
f
3
340 (NH), 1610, 1519, 1464. PMR spectrum (400 MHz, CDCl , ꢅ, ppm, J/Hz): 1.38–1.52 (4H, m, H-3ꢃ, 4ꢃ), 1.65–1.78 (4H,
3
m, H-2ꢃ, 5ꢃ), 2.60 (2H, m, H-4), 2.66 (2H, m, H-4), 2.89 (2H, m, H-3), 3.15 (2H, m, H-3), 3.776 (6H, s, OCH ), 3.780 (6H, s,
3
*
*
OCH ), 3.82 (2H, m, H-1), 6.50 (2H, s, H-8), 6.54 (2H, s, H-5).
3
1
,5-bis-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)pentane (5b), C H N O , was prepared from 3b
27 38 2 4
(
0.5 g, 0.001 mol) and POCl (1.5 mL). Yield 80% (0.39 g), mp of dihydrochloride 220–224°C (Me CO), R 0.68 (system 2).
3
2
f
–
1
IR spectrum (ꢄ, cm ): 3423 (NH), 1613, 1519, 1460. PMR spectrum (400 MHz, CDCl , ꢅ, ppm, J/Hz): 1.35–1.50 (6H, 2m,
3
H-3ꢃ, 4ꢃ, 5ꢃ), 1.65–1.75 (4H, m, H-2ꢃ, 5ꢃ), 2.60 (2H, m, H-4), 2.68 (2H, m, H-4), 2.90 (2H, m, H-3), 3.16 (2H, m, H-3), 3.770
*
*
(
6H, s, OCH ), 3.774 (6H, s, OCH ), 3.86 (2H, m, H-1), 6.49 (2H, s, H-8), 6.53 (2H, s, H-5).
3 3
1
,7-bis-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)heptane (5c), C H N O , was prepared from 3c
29 42 2 4
(
0.5 g, 0.001 mol) and POCl (1.5 mL). Yield 67.4% (0.31 g), mp of dihydrochloride 163–166°C (Me CO), R 0.6 (system 2).
3
2
f
–
1
IR spectrum (ꢄ, cm ): 3429 (NH), 1613, 1519, 1464. PMR spectrum (400 MHz, CDCl , ꢅ, ppm, J/Hz): 1.3–1.5 (10H, 2m,
3
H-3ꢃ, 4ꢃ, 5ꢃ, 6ꢃ, 7ꢃ), 1.65–1.85 (4H, m, H-2ꢃ, 8ꢃ), 2.65 (2H, m, H-4), 2.80 (2H, m, H-4), 2.95 (2H, m, H-3), 3.25 (2H, m, H-3),
*
*
3
.781 (6H, s, OCH ), 3.776 (6H, s, OCH ), 3.98 (2H, m, H-1), 4.67 (2H, s, NH), 6.50 (2H, s, H-8), 6.53 (2H, s, H-5).
3 3
303

1
,8-bis-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)octane (5d), C H N O , was prepared from 3d
30 44 2 4
(
0.5 g, 0.001 mol) and POCl (1.5 mL). Yield 70% (0.33 g), mp of dihydrochloride 240–244°C (Me CO), R 0.6 (system 2).
3
2
f
PMR spectrum (400 MHz, CDCl , ꢅ, ppm, J/Hz): 1.10–1.24 (12H, m, H-3ꢃ, 4ꢃ, 5ꢃ, 6ꢃ, 7ꢃ, 8ꢃ), 1.6–1.8 (4H, m, H-2ꢃ, 9ꢃ), 2.55–2.75
3
*
(
(
4H, m, H-4), 2.90 (2H, m, H-3), 3.15 (2H, m, H-3), 3.776 (6H, s, OCH ), 3.783 (6H, s, OCH ), 3.8–3.9 (2H, m, H-1), 6.50
3 3
*
2H, s, H-8), 6.54 (2H, s, H-5).
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1.
M. Shamma, The Isoquinoline Alkaloids. Chemistry and Pharmacology, Vol. 25, Academic Press, New York, London,
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304