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Article

Synthesis and Contractile Activity of Substituted 1,2,3,4-Tetrahydroisoquinolines

by
Iliyan Ivanov
1,*,
Stoyanka Nikolova
1,
Dimo Aladjov
1,
Iliyana Stefanova
2 and
Plamen Zagorchev
2,*
1
Department of Organic Chemistry, University of Plovdiv, 24 Tzar Assen Street, 4000 Plovdiv, Bulgaria
2
Department of Biophysics, Medical University, 15A Vasil Aprilov Street, 4000 Plovdiv, Bulgaria
*
Authors to whom correspondence should be addressed.
Molecules 2011, 16(8), 7019-7042; https://doi.org/10.3390/molecules16087019
Submission received: 22 July 2011 / Revised: 10 August 2011 / Accepted: 11 August 2011 / Published: 16 August 2011
(This article belongs to the Special Issue Heterocycles)
Browse Figures
Versions Notes

Abstract

:
A series of different 1-monosubstituted and 1,1-disubstituted 1,2,3,4-tetrahydro-isoquinolines was synthesized in high yields from different ketoamides. We have developed a convenient method for the synthesis of disubstituted derivatives by interaction of ketoamides with organomagnesium compounds, followed by cyclization in the presence of catalytic amounts of p-toluenesulfonic acid (PTSA). A number of substituents at the C-1 in the isoquinoline skeleton were introduced varying either carboxylic acid or organomagnesium compound. Some of the obtained 1,1-dialkyl-1,2,3,4-tetrahydro-isoquinolines possess contractile activity against guinea pig’s gastric smooth muscle preparations.

Graphical Abstract

1. Introduction

The pharmacological activity of certain tetrahydroisoquinolines has long been established [1]. The tetrahydroisoquinoline motif is present in a variety of natural products, including cactus alkaloids (peyoruvic acid) [2], mammalian alkaloids (salsoline carboxylic acid) [3,4,5], the esteinascidine family (ET743) [6,7,8,9] and spiro-benzoisoquinoline alkaloids (parfumine) [10,11]. Within the series of 1-substituted 6,7-dihydroisoquinolines there are several active sympathomimetic amines [12,13], one of which, trimetoquinol, is a potent bronchodilator [14,15]. Ohkubo and co-workers [16] synthesized a series of 1,2,3,4-tetrahydroisoquinolines, for example MK801 (disocilpine), and evaluated them for anticonvulsant activity against intracerebro-ventriculas N-methyl-D-aspartate (NMDA)-induced seizures in mice [17,18,19,20]. The authors [16] found that (+)-1-methyl-1-phenyl-1,2,3,4-tetrahydroiso-quinoline hydrochloride [(+)-FR115427)] was the most effective anticonvulsant, protected CA1 hippocampal neuronal degeneration in rats and also showed anti-hypoxic activity in mice. Some isoquinoline derivatives, specially 1,1-dialkyl-1,2,3,4-tetrahydroisoquinolines, have been found to have a peripheral vasodilatory effect, a sympathetic nerve stimulating effect, an analgesic effect, or an anticonvulsant effect, and a few of them have become available clinically [21]. The biological tests indicate that 1,1-dialkyl-1,2,3,4-tetrahydroisoquinolines have potent dopamine D2 receptor-blocking activity and an excellent safety profile. 1,1-Disubstituted tetrahydroisoquinoline derivatives, also were found in Aristolichia species (Aristolochiaceae). [22]. Kubota et al. [23] also synthesized different N-acyl 1,2,3,4-tetrahydroisoquinoline derivatives and evaluated their pharmacological activity as novel specific bradycardic agents.
The variety of biological activities of substituted 1,2,3,4-tetrahydroisoquinolines prompted us to synthesized a number of their derivatives. The most appropriate method for their synthesis is the Pictet-Spengler reaction. However, this classical reaction has some disadvantages, the main one of which is the ring closure after condensation of phenethylamines with an aldehyde in the classical variant (aldehydes give good yields while ketones tend not to give products at all). However, in the last several years 1,1-disubstituted tetrahydroisoquinolines have been synthesized from starting cyclic ketones using titanium(IV)isopropoxide and acetic-formic anhydride [24]. Later, Kumpaty [25] reported a selective and direct access to secondary amines by reductive mono-N-alkylation of primary amines in the presence of the Ti(i-PrO)4 and NaBH4. A new, environmentally friendly variation of the Pictet-Spengler reaction has been elaborated using a small pore size zeolite, Ersorb 4 [26]. Some authors have reported the synthesis and an application of a new planar-chiral Lewis acid based on a 1,2-azaborolyl framework [27]. Pictet-Spengler condensation of dopamine with (+)-menthyl pyruvate followed by acid hydrolysis furnished (-)-R-salsolinol-1-carboxylic acid in good yield [28,29,30]. The basic method, described in literature is preparation of 1,l-dimethyltetrahydroisoquinoline from 3,4-dihydro-6,7-dimethoxy-1-methylisoquinoline [31]. Recently Kałuza and co-workers described a facile synthesis of highly substituted, optically pure tetraydroisoquinolines with a quaternary carbon stereocenter [32]. Funabashi et al. [33] reported the first example of a catalytic enantioselective quaternary stereocenter construction through a Reissert-type reaction with quinolines, using a bifunctional catalyst. 1-Substituted isoquinolines or 3,4-dihydroisoquinolines were used as starting materials for the synthesis of Reisert compounds [34,35,36,37,38]. Stereodivergent synthesis of 1,10-cis- and -trans-thiazolo[4,3-a]isoquinolinones, starting from N-4,3-dimethoxyphenethylthiazolidinedione and using N-acyliminium ion or Parham cyclization, also was reported recently [39]. Kirkpatrick and Maclaren prepared 1,1,-disubstituted 1,2,3,4-tetrahydro-b-carbolines by action of trifluoracetic acid on enamines of tryptamine or tryptophan [40]. Later Bobowski [41,42] reported condensation of 1H-indole-3-ehtanamines with different 2,4-pentanediones and b-keto esters, followed by acid-catalyzed ring closure of resulting enamines to corresponding 1,1-disubtituted indoles.

2. Results and Discussion

The biological activity of isoquinoline derivatives, as analogues of various drugs, has provided great deal of interest for the synthesis of new compounds. Papaverine, for example, is a smooth muscle relaxant and vasodilator which acts directly on the heart muscle. The biological activity of papaverine attracted a great deal of our interest for the synthesis and investigations of 1-substituted isoquinoline derivatives, as potential new drugs.
We report herein an alternative of the classical methods which includes ortho-acylation of 2-phenethylamines in polyphosphoric acid and following cyclization. In our previous reports we applied this protocol for the synthesis of variety O- and N-heterocycles and alkaloids [43,44,45,46,47]. Our synthetic approach to 1- and 1,1-disubstituted 1,2,3,4-tetrahydroisoquinolines is depicted in the Scheme 1, which shows the key steps as well as the main starting material.
Molecules 16 07019 g004 550
Scheme 1. Retrosynthetic scheme for the synthesis of both 1-monosubstituted and 1,1-disubstituted 1,2,3,4-tetrahydroisoquinolines.
Scheme 1. Retrosynthetic scheme for the synthesis of both 1-monosubstituted and 1,1-disubstituted 1,2,3,4-tetrahydroisoquinolines.
Molecules 16 07019 g004
Our strategy is based on the acylation of the amides of homoveratrylamine 1 with carboxylic acids and application of obtained ketoamides 3 for the preparation of 1-substituted 6 or 1,1-disubstited 1,2,3,4-tetrahydroisoquinolines 7. Starting ketoamides of homoveratrylamine 3 were obtained by Friedel-Crafts-type acylation. The Friedel-Crafts acylation of activated benzene rings in the presence of polyphosphoric acid (PPA) is a very convenient method for direct synthesis of aromatic ketones [43], 1-substituted 3,4-dihydroisoquinolines [44], 1-substituted 3,4-dihydro-b-carbolines [45], quinazolinones [46], isochromanes [47], etc. The reaction of amides of homoveratrylamine 1 with acetic anhydride, benzoic or phenylacetic acid 2 in PPA gave the expected ketoamides 3 in high yield (Scheme 2, Table 1).
Molecules 16 07019 g005 550
Scheme 2. Synthesis of starting ketoamides.
Scheme 2. Synthesis of starting ketoamides.
Molecules 16 07019 g005
Table
Table 1. Reaction conditions and yields for starting ketoamides 3.
Table 1. Reaction conditions and yields for starting ketoamides 3.
3R1R2Reaction conditionsmp, °CYield [%]
aСОCH3CH32 h, 80 °С124–12592
bCOC6H5CH32 h, 80 °С147–14880
cCOCH2C6H5CH32 h, 80 °С135–13779
dCOOC2H5CH33 h, 80 °С90–90.595
eSO2CH3CH32 h, 80 °С140–14175
fCONHC6H5CH32 h, 60 °С118–12175
gСОCH3C6H52 h, 80 °С212–21387
hCOC6H5C6H52 h, 80 °С117–12185
iCOCH2C6H5C6H54 h, 60 °С108–11189
jCOOC2H5C6H53 h, 80 °С97–9889
kSO2CH3C6H53h, 80 °C84–8683
lCONHC6H5C6H54 h, 60 °С128–13176
mСОCH3CH2C6H520 h, 60 °С188–18962
nCOC6H5CH2C6H520 h, 60 °С141–141.582
Molecules 16 07019 g006 550
Scheme 3. Synthesis of 1-substituted and 1,1-disubstituted-1,2,3,4-tetrahydroisoquinolines.
Scheme 3. Synthesis of 1-substituted and 1,1-disubstituted-1,2,3,4-tetrahydroisoquinolines.
Molecules 16 07019 g006
The next step in our synthesis was application of acylated ketoamides for the construction of isoquinoline ring system. We anticipated that 1-substituted 1,2,3,4-tetrahydroisoquinolines could be prepared trough reduction of ketoamides followed by cyclization of newly obtained hydroxyamides through p-toluenesulfonic acid. Respectively, 1,1-disubstituted 1,2,3,4-tetrahydroisoquinolines could be prepared from 4 and 5, obtained from ketoamides and Grignard reagents (Scheme 3).
For the next step, 3 were reduced with NaBH4 in methanol to give corresponding 4 with 85–90% yields (Table 2).
Table
Table 2. Synthesis of hydroxyamides 4.
Table 2. Synthesis of hydroxyamides 4.
4R1R2Yield [%]mp, °C
aСОCH3CH395108–110
bCOC6H5CH394109–110
cCOCH2C6H5CH392oil
dCOOC2H5CH39285–87
eSO2CH3CH390oil
fCONHC6H5CH391147–150
gСОCH3C6H594133–135
hCOC6H5C6H59058–60
iCOCH2C6H5C6H591oil
jCOOC2H5C6H59192–95
kSO2CH3C6H590oil
lCONHC6H5C6H59073–75
mСОCH3CH2C6H595oil
nCOC6H5CH2C6H591117–118
Compounds 5 were prepared with good (50–56%) yields from starting ketoamides 3 and 5-fold excess of magnesium and equimolar amounts of alkyl- (or aryl-) halide. Reaction proceeded at room temperature in dry ether (Table 3).
Table
Table 3. Reaction of ketoamides with Grignard reagents.
Table 3. Reaction of ketoamides with Grignard reagents.
5R1R2R3Yield [%]mp, °C
aСОCH3CH3CH352oil
bCOC6H5CH3CH350160–162
cCOCH2C6H5CH3CH350oil
dCOOC2H5CH3CH3- *-
eSO2CH3CH3CH3- *-
nCOC6H5CH2C6H5CH35048–50
oСОCH3CH3C2H5- *-
pCOC6H5CH3C2H565131–135
rSO2CH3CH3C2H5- *-
sCOC6H5CH3C6H55096–98
tSO2CH3C6H5C2H551131–134
* compounds were directly cyclized.
The next step was cyclization of the newly synthesized compounds 4 and 5. We found that 4 in the presence of a catalytic amount of toluene-p-sulfonic acid for 30 min at rt in dichloromethane afforded the corresponding 1,2,3,4-tetrahydroisoquinolines 6 with high yield 90–97% (Table 4).
Table
Table 4. Synthesis of 1-substituted 1,2,3,4-tetrahydroisoquinolines.
Table 4. Synthesis of 1-substituted 1,2,3,4-tetrahydroisoquinolines.
6R1R2Yield [%]mp, °C
aСОCH3CH39497–98
bCOC6H5CH390126–127
cCOCH2C6H5CH392115–116
dCOOC2H5CH39072–74
eSO2CH3CH392105–106
fCONHC6H5CH391178–180
gСОCH3C6H594109–191
hCOC6H5C6H593143–144
iCOCH2C6H5C6H595oil
jCOOC2H5C6H588oil
kSO2CH3C6H590183–184
lCONHC6H5C6H589120–122
mСОCH3CH2C6H591102–105
nCOC6H5CH2C6H594189–192
The same protocol can be readily used for the cyclization to 1,1-disubstituted 1,2,3,4-tetrahydro-isoquinolines 7 (Table 5).
Table
Table 5. Cyclisation to 1,1-disubstituted 1,2,3,4-tetrahydroisoquinolines.
Table 5. Cyclisation to 1,1-disubstituted 1,2,3,4-tetrahydroisoquinolines.
7R1R2R3Yield [%]mp, °C
aСОCH3CH3CH396123–125
bCOC6H5CH3CH397143–146
cCOCH2C6H5CH3CH397oil
dCOOC2H5CH3CH39055-56
eSO2CH3CH3CH395123–125
nCOC6H5CH2C6H5CH330164–166
oСОCH3CH3C2H56076–81
pCOC6H5CH3C2H58090–92
rSO2CH3CH3C2H560100–102
sCOC6H5CH3C6H560103–133
tSO2CH3C6H5C2H560138–141
We also found that when the substituent at the C-1 is ethyl or benzyl (in some cases also methyl), the styrene products 8 were formed also than expected cyclic 1,1-disubtituted product 7 (Scheme 4, Table 6).
Molecules 16 07019 g007 550
Scheme 4. Formation of styrenes 8.
Scheme 4. Formation of styrenes 8.
Molecules 16 07019 g007
Table
Table 6. Formation of styrenes.
Table 6. Formation of styrenes.
8R1R2R3Yield [%]mp, °C
gCOC6H5CH3CH36572–75
nCOC6H5CH3C6H55048–50
sCOC6H5C6H5H5096–98
tSO2CH3C6H5CH330145–148

2.1. Estimation of Gastric Smooth Muscle Contractile Activity for Some of the Newly Synthesized Compounds

The experiments were performed on gastric corpus smooth muscle preparations obtained from adult male guinea-pig. All experimental procedures were done in strict accordance with the current European regulations (86/609/EEC) regarding the protection of animals used for experimental purposes. The spontaneous contractile activity of the smooth-muscle strips were measured with the help of a tensotransducer measuring system at isometric conditions.
The biological activity of papaverine attracted a great deal of our interest for the synthesis and investigations of 1- and 1,1-disubstituted isoquinoline derivatives, as potential new drugs. The target compounds, being structural analogues of known bioactive leads, as papaverine and cryptostiline, are expected to show biological activity. For this purpose we tested three main groups of compounds for contractile activity. In search of the reason for activity, firstly we estimated 1,2,3,4-tetrahydroisoquinoline skeleton and 1-methyl- and 1-phenyl-6,7-dimetoxy-1,2,3,4-tetrahydroisoquinolines. We found that the absence of substituents devoided the compounds of contractile activity, as shown in Figure 1. The isoquinoline derivatives were less effective in contractile smooth muscle activity (−0.5%, +7.5% and +10.3% vs. control, respectively).
The second group included 1,1-disubstituted-6,7-dimetoxy-1,2,3,4-tetrahydroisoquinolines. The estimation of contractile activity showed that tested compounds have similar effect, as papaverine. The isoquinoline derivatives 7e and 7r were most effective in contractile smooth muscle activity (−74% and −43% vs. control, respectively) (Figure 2).
Molecules 16 07019 g001 550
Figure 1. Change of spontaneous contractile activity of gastric smooth muscles preparation after using 1-substituted 1,2,3,4-tetrahydroisoquinoline derivatives and papaverine, normal activity is taken for 100%.
Figure 1. Change of spontaneous contractile activity of gastric smooth muscles preparation after using 1-substituted 1,2,3,4-tetrahydroisoquinoline derivatives and papaverine, normal activity is taken for 100%.
Molecules 16 07019 g001
Molecules 16 07019 g002 550
Figure 2. Change of spontaneous contractile activity of gastric smooth muscles preparation after using 1,1-disubstituted 1,2,3,4-tetrahydroisoquinoline derivatives and papaverine, normal activity is taken for 100%.
Figure 2. Change of spontaneous contractile activity of gastric smooth muscles preparation after using 1,1-disubstituted 1,2,3,4-tetrahydroisoquinoline derivatives and papaverine, normal activity is taken for 100%.
Molecules 16 07019 g002
The third group included styrene products 8. As shown in Figure 3, styrenes 8s and 8t were most effective in contractile smooth muscle activity (−41% and −45% vs. control, respectively) (Figure 3). The contractile activity against smooth muscle preparations of these compounds were not as high as the activity of 7.
Molecules 16 07019 g003 550
Figure 3. Change of spontaneous contractile activity of gastric smooth muscles preparation after using styrenes and papaverine, normal activity is taken for 100%.
Figure 3. Change of spontaneous contractile activity of gastric smooth muscles preparation after using styrenes and papaverine, normal activity is taken for 100%.
Molecules 16 07019 g003

3. Experimental

Reagents and chemicals were purchased from commercial sources (Sigma-Aldrich S.A. and Riedel-de Haën) and used as received. Melting points were determined on a Boetius hot stage apparatus and are uncorrected. Spectra were recorded on a Bruker Avance DRX250 spectrometer. 1H-NMR and 13C-NMR spectra were taken in CDCl3 (unless otherwise specified) at 250 or 600 MHz and 62.5 MHz respectively. Chemical shifts were given in part per million (ppm) relative and were referenced to TMS (δ = 0.00 ppm) as an internal standard and coupling constants are indicated in Hz. All the NMR spectra were taken at rt (ac. 295 K). Elemental analyses were performed with a TruspecMicro. TLC was carried out on precoated 0.2 mm Fluka silica gel 60 plates, using diethyl ether:n-hexane:1:1 as the eluent system. Merck silica gel 60 (0.063–0.2 mm) was used for column chromatographic separation. Polyphosphoric acid was obtained from 85% phosphoric acid and P2O5 (1:1 w/w).

3.1. Typical Procedure for Preparation of N-[2-(2-Acyl-4,5-dimethoxyphenyl)-ethyl]amides 3

To a solution of amide 1 (3 mmol) and the corresponding carboxylic acid or their anhydrides 2 (5 mmol) in dichloromethane (10 mL) in an open flask polyphosphoric acid (7 g) was added. The mixture was stirred on a mechanical stirrer carefully at 60 °C or 80 °C then poured on crushed ice and extracted with CH2Cl2 (3 × 20 mL). The combined extracts were dried (Na2SO4), filtered on the short column filled with neutral Al2O3 and then concentrated.
N-(2-Acetyl-4,5-dimethoxyphenethyl)acetamide (3a): known compound [53,54,55,56].
N-(2-Acetyl-4,5-dimethoxyphenethyl)benzamide (3b): 1H-NMR: 2.61 (s, 3H), 3.10 (t, J = 6.4, 2H), 3.75 (dt, J = 6.6, 5.4, 2H), 3.88 (s, 3H), 3.90 (s, 3H), 6.80 (broad s, 1H, NH), 7.16 (s, 1H), 7.28 (s, 1H), 7.34–7.47 (m, 4H), 7.77–7.80 (m, 1H); 13C-NMR: 201.5, 181.6, 167.4, 152.1, 146.8, 134.5, 131.0, 128.3, 126.9, 114.0, 112.6, 56.1, 55.9, 42.4, 32.1, 29.4. Anal. calcd. for C19H21NO4: C, 69.71; H, 6.47; N, 4.28. Found: C, 69.87; H, 6.58; N, 4.18.
N-(2-Acetyl-4,5-dimethoxyphenethyl)-2-phenylacetamide (3c): 1H-NMR: 2.51 (s, 3H), 2.95 (t, J = 6.8, 2H), 3.47 (s, 2H), 3.51 (dd, J = 7.0, 5.2, 2H), 3.89 (s, 3H), 3.92 (s, 3H), 6.43 (broad s, 1H, NH), 6.70 (s, 1H), 7.12 (s, 1H), 7.14–7.27 (m, 5H); 13C-NMR: 200.3, 181.6, 171.2, 152.0, 146.7, 135.0, 134.3, 129.3, 128.7, 128.6, 126.9, 114.1, 112.97, 56.2, 55.97, 43.8, 41.5, 32.5, 29.2. Anal. calcd. for C20H23NO4: C, 70.36; H, 6.79; N, 4.10. Found: C, 70.48; H, 6.95; N, 3.90.
Ethyl 2-acetyl-4,5-dimethoxyphenethylcarbamate (3d): 1H-NMR: 1.21 (t, J = 7.1, 3H), 2.58 (s, 3H), 3.03 (t, J = 6.9, 2H), 3.43 (dd, J = 12.7, 6.6, 2H), 3.92 (s, 3H), 3.93 (s, 3H), 4.08 (q, J = 7.1, 2H), 5.31 (broad s, 1H, NH), 6.75 (s, 1H), 7.22 (s, 1H); 13C-NMR: 200.0, 156.7, 151.8, 146.8, 134.4, 129.7, 114.3, 113.2, 60.5, 56.3, 55.9, 42.5, 33.9, 29.3, 14.6. Anal. calcd. for C15H21NO5: C, 61.00; H, 7.17; N, 4.74. Found: C, 61.25; H, 7.45; N, 4.54.
N-(2-Acetyl-4,5-dimethoxyphenethyl)methanesulfonamide (3e): 1H-NMR (DMSO): 2.53 (s, 3H), 2.82 (s, 3H), 2.94 (t, J = 7.2, 2H), 3.12 (dd, J = 7.4, 6.1, 2H), 3.80 (s, 3H), 3.81 (s, 3H), 6.89 (s, 1H), 6.98 (t, J = 5.6, 1H, NH), 7.35 (s, 1H); 13C-NMR: 200.6, 151.5, 146.8, 133.1, 129.7, 115.1, 114.1, 56.1, 55.9, 44.2, 39.6, 34.1, 29.8. Anal. calcd. for C13H19NO5S: C, 51.81; H, 6.35; N, 4.65; S, 10.64. Found: C, 51.96; H, 6.15; N, 4.72; S, 10.45.
1-(2-Acetyl-4,5-dimethoxyphenethyl)-3-phenylurea (3f): 1H-NMR: 2.42 (s, 3H), 2.56 (s, 1H, CONH), 2.91 (dd, J = 6.5, 7.9, 2H), 3.28 (td, J = 6.4, 7.3, 2H), 3.73 (s, 3H), 3.75 (s, 3H), 5.78 (t, J = 5.8, 1H, NHCO), 6.64 (s, 1H), 6.77 (tt, J = 1.1, 7.7, 1H), 7.05 (dd, J = 1.6, 6.8, 1H), 7.09 (s, 1H), 7.26 (dd, J = 3.4, 5.6, 2H), 7.83 (s, 1H); 13C-NMR: 199.7, 156.1, 151.7, 146.6, 140.0, 134.7, 129.3, 128.7, 121.7, 118.6, 114.6, 113.4, 56.1, 55.9, 41.3, 34.8, 29.4. Anal. calcd. for C19H22N2O4: C, 66.65; H, 6.48; N, 8.18. Found: C, 66.86; H, 6.28; N, 8.32.
N-(2-Benzoyl-4,5-dimethoxyphenethyl)acetamide (3g): 1H-NMR: 1.95 (s, 3H), 2.86-2.88 (m, 2H), 3.59–3.52 (m, 2H), 3.80 (s, 3H), 3.97 (s, 3H), 6.84 (s, 1H), 6.89 (s, 1H), 7.01 (broad s, 1H, NH), 7.54–7.45 (m, 2H), 7.66–7.58 (m, 1H), 7.85–7.81 (m, 2H); 13C-NMR: 198.2, 170.6, 151.4, 146.5, 138.0, 133.4, 130.5, 130.3, 129.96, 128.5, 128.3, 113.3, 112.9, 56.2, 56.1, 41.9, 31.8, 23.2. Anal. calcd. for C19H21NO4: C, 69.71; H, 6.47; N, 4.28. Found: C, 69.98; H, 6.29; N, 4.34.
N-(2-Benzoyl-4,5-dimethoxyphenethyl)benzamide (3h): known compound [48].
N-(2-Benzoyl-4,5-dimethoxyphenethyl)-2-phenylacetamide (3i): 1H-NMR: 2.84 (t, J = 6.7, 2H), 3.51 (s, 2H), 3.56–3.60 (m, 2H), 3.80 (s, 3H), 3.95 (s, 3H), 6.76 (broad s, 1H, NH), 6.80 (s, 1H), 6.84 (s, 1H), 7.29–7.15 (m, 5H), 7.52–7.46 (m, 2H), 7.62–7.59 (m, 1H), 7.77–7.74 (m, 2H); 13C-NMR: 197.5, 171.3, 151.3, 146.3, 138.1, 135.1, 133.1, 130.4, 129.9, 129.3, 128.6, 128.4, 126.9, 113.2, 113.1, 56.1, 56.0, 43.8, 41.6, 31.6. Anal. calcd. for C25H25NO4: C, 74.42; H, 6.25; N, 3.47. Found: C, 74.78; H, 6.37; N, 3.25.
Ethyl 2-benzoyl-4,5-dimethoxyphenethylcarbamate (3j): known compound [44].
N-(2-Benzoyl-4,5-dimethoxyphenethyl)methanesulfonamide (3k): 1H-NMR: 2.79 (s, 3H), 2.94 (t, J = 6.6, 2H), 3.48 (ddd, J = 2.2, 5.9, 6.5, 2H), 3.79 (s, 3H), 3.99 (s, 3H), 5.66 (t, J = 5.1, 1H, NH), 6.87 (s, 1H), 6.91 (s, 1H), 7.49 (tdd, J = 1.4, 6.6, 8.2, 2H), 7.59–7.66 (m, 1H), 7.79 (t, J=1.8, 1H), 7.82 (t, J = 1.4, 1H); 13C-NMR: 197.7, 151.5, 146.6, 138.0, 133.2, 132.6, 130.4, 130.1, 128.4, 113.5, 58.7, 56.1, 45.0, 39.7, 32.9. Anal. calcd. for C18H21NO5S: C, 59.49; H, 5.82; N, 3.85; S, 8.82. Found: C, 59.70; H, 5.95; N, 3.64; S, 8.61.
1-(2-Benzoyl-4,5-dimethoxyphenethyl)-3-phenylurea (3l): 1H-NMR: 2.87 (t, J = 6.9, 2H), 3.51 (q, J = 6.8, 2H), 3.74 (s, 3H), 3.90 (s, 3H), 5.92 (t, J = 4.9, 1H, NHCO), 6.83 (s, 1H), 6.87 (s, 1H), 6.99 (tt, J = 1.3, 7.7, 1H), 7.08 (broad s, 1H, CONH), 7.18–7.31 (m, 4H), 7.44 (tt, J = 1.4, 6.8, 2H), 7.54–7.61 (m, 1H), 7.74–7.77 (m, 2H); 13C-NMR: 198.0, 156.0, 151.4, 146.4, 139.1, 138.2, 133.6, 133.1, 130.4, 129.9, 128.9, 128.4, 123.0, 120.3, 113.6, 113.3, 56.1, 56.0, 42.4, 33.3. Anal. calcd. for C24H24N2O4: C, 71.27; H, 5.98; N, 6.93. Found: C, 71.49; H, 6.19; N, 6.87.
N-(4,5-Dimethoxy-2-(2-phenylacetyl)phenethyl)acetamide (3m): known compound [44].
N-(4,5-Dimethoxy-2-(2-phenylacetyl)phenethyl)benzamide (3n): known compound [44].

3.2. Typical Procedure for the Preparation of Compounds 4a-n

To solution of the corresponding ketoamide 3 (1 mmol) in methanol (15 mL), NaBH4 (2 mmol, 0.1 g) was added portionwise. The solution was stirred 30 min at room temperature, than the solvent was removed under vacuum. Water (30 mL) was added to the residue and the solution was extracted with CH2Cl2 (3 × 20 mL), then the combined extracts were dried (Na2SO4). The products, after evaporation of the solvent, were obtained with 85–90% yields.
N-(2-(1-Hydroxyethyl)-4,5-dimethoxyphenethyl)acetamide (4a): 1H-NMR: 1.48 (d, J = 6.4, 3H), 1.85 (s, 3H), 2.72 (td, J = 7.1, 14.0, 1H), 2.86 (td, J = 6.9, 13.9, 1H), 3.13 (broad s, 1H, OH), 3.32 (td, J = 6.9, 13.3, 1H), 3.49 (td, J = 7.0, 13.4, 1H), 3.82 (s, 3H), 3.85 (s, 3H), 5.07 (q, J = 6.4, 1H), 6.28 (t, J = 4.6, 1H, NH), 6.60 (s, 1H), 7.00 (s, 1H); 13C-NMR: 170.5, 148.0, 147.8, 135.8, 127.9, 112.9, 108.9, 65.8, 55.9, 55.88, 41.0, 31.6, 24.4, 23.0. Anal. calcd. for C14H21NO4: C, 62.90; H, 7.92; N, 5.24. Found: C, 63.15; H, 8.06; N, 5.13.
N-(2-(1-Hydroxyethyl)-4,5-dimethoxyphenethyl)benzamide (4b): 1H-NMR: 1.84 (s, 3H), 2.07 (broad s, 1H, OH), 2.72 (td, J = 7.2, 14.1, 1H), 2.90 (td, J = 7.2, 14.1, 1H), 3.27–3.51 (m, 2H), 3.75 (s, 3H), 3.86 (s, 3H), 6.04 (d, J = 1.7, 1H), 6.18 (t, J = 4.9, 1H, NH), 6.67 (s, 1H), 6.83 (s, 1H), 7.25–7.35 (m, 5H); 13C-NMR: 170.6, 148.8, 147.5, 143.8, 134.2, 129.1, 128.3, 127.2, 126.5, 113.0, 111.4, 72.4, 55.9, 55.8, 40.9, 31.7, 22.9. Anal. calcd. for C19H23NO4: C, 69.28; H, 7.04; N, 4.25. Found: C, 69.43; H, 7.25; N, 4.13.
N-(2-(1-Hydroxyethyl)-4,5-dimethoxyphenethyl)-2-phenylacetamide (4c): 1H-NMR: 1.44 (d, J = 6.4, 3H), 2.76 (ddd, J = 7.1, 14.3, 32.3, 2H), 3.08 (broad s, 1H, OH), 3.43 (dtd, J = 7.4, 13.6, 13.4, 20.6, 2H), overpalled with 3.43 (s, 2H), 3.78 (s, 3H), 3.85 (s, 3H), 5.02 (q, J = 6.3, 6.4, 1H), 6.09 (t, J = 5.6, 1H, NH), 6.52 (s, 1H), 6.99 (s, 1H), 7.11–7.15 (m, 2H), 7.24–7.31 (m, 3H); 13C-NMR: 171.2, 147.8, 147.7, 135.9, 134.7, 129.2, 128.7, 127.5, 127.0, 112.8, 108.9, 65.6, 55.8, 43.4, 40.7, 31.4, 24.2. Anal. calcd. for C20H25NO4: C, 69.95; H, 7.34; N, 4.08. Found: C, 70.15; H, 7.53; N, 3.96.
Ethyl2-(1-hydroxyethyl)-4,5-dimethoxyphenethylcarbamate (4d): 1H-NMR: 1.19 (t, J = 7.1, 3H), 1.47 (d, J = 6.4, 3H), 2.62-2.90 (m, 2H), 3.36 (tt, J = 6.9, 13.6, 2H), 3.84 (s, 3H), 3.86 (s, 3H), 4.05 (q, J = 7.1, 2H), 4.92 (broad s, 1H, NH), 5.10 (q, J = 6.3, 1H), 6.60 (s, 1H), 7.03 (s, 1H); 13C-NMR: 156.8, 148.0, 148.0, 136.1, 127.4, 112.9, 108.8, 65.9, 60.8, 55.93, 55.91, 42.2, 32.4, 24.6, 14.6. Anal. calcd. for C15H23NO5: C, 60.59; H, 7.80; N, 4.71. Found: C, 60.73; H, 7.98; N, 4.56.
N-(2-(1-Hydroxyethyl)-4,5-dimethoxyphenethyl)methanesulfonamide (4e): 1H-NMR: 1.48 (d, J = 6.4, 3H), 1.91 (broad s, 1H, OH), 2.74 (s, 3H), 2.82 (td, J = 3.9, 6.7, 2H), 3.22–3.42 (m, 2H), 3.84 (s, 3H), 3.86 (s, 3H), 5.06 (q, J = 6.4, 1H), 5.31 (t, J = 6.5, 1H, NH), 6.65 (s, 1H), 6.99 (s, 1H); 13C-NMR: 148.3, 148.0, 135.7, 127.4, 112.9, 109.1, 66.0, 56.0, 55.9, 44.6, 39.9, 32.2, 24.4. Anal. calcd. for C13H21NO5S: C, 51.47; H, 6.98; N, 4.62; S, 10.57. Found: C, 51.68; H, 7.18; N, 4.44; S, 10.69.
1-(2-(1-Hydroxyethyl)-4,5-dimethoxyphenethyl)-3-phenylurea (4f): 1H-NMR: 1.43 (d, J = 6.4, 3H), 2.76 (q, J = 6.9, 1H), 2.87 (td, J = 7.1, 14.1, 1H), 3.31 (td, J = 7.0, 12.4, 1H), 3.58 (dq, J = 6.5, 13.3, 1H), 3.83 (s, 3H), 3.87 (s, 3H), 5.10 (dq, J = 3.5, 6.3, 1H), 5.80 (t, J = 5.7, 1H, NH), 6.66 (s, 1H), 6.93 (tt, J = 1.1, 7.5, 1H), 7.11 (s, 1H), 7.18–7.25 (m, 2H), 7.35 (dd, J = 1.1, 8.6, 2H); 13C-NMR: 155.7, 147.4, 147.3, 139.6, 136.8, 128.3, 127.6, 121.4, 118.2, 112.4, 108.6, 65.0, 55.5, 40.8, 31.8, 24.5. Anal. calcd. for C19H24N2O4: C, 66.26; H, 7.02; N, 8.13. Found: C, 66.47; H, 7.15; N, 8.01.
N-(2-(Hydroxy(phenyl)methyl)-4,5-dimethoxyphenethyl)acetamide (4g): 1H-NMR: 1.84 (s, 3H), 2.07 (broad s, 1H, OH), 2.72 (td, J = 7.2, 14.1, 1H), 2.90 (td, J = 6.8, 13.8, 1H), 3.27–3.51 (m, 2H), 3.75 (s, 3H), 3.86 (s, 3H), 6.04 (d, J = 1.7, 1H), 6.18 (t, J = 4.9, 1H, NH), 6.68 (s, 1H), 6.83 (s, 1H), 7.25–7.39 (m, 5H); 13C-NMR: 170.6, 148.3, 147.5, 143.7, 134.2, 129.1, 128.3, 127.2, 126.5, 113.0, 111.4, 72.4, 56.0, 55.8, 40.9, 31.7, 23.0. Anal. calcd. for C19H23NO4: C, 69.28; H, 7.04; N, 4.25. Found: C, 69.19; H, 7.24; N, 4.37.
N-(2-(Hydroxy(phenyl)methyl)-4,5-dimethoxyphenethyl)benzamide (4h): 1H-NMR: 1.81 (broad s, 1H, OH), 2.86 (td, J = 7.2, 14.3, 1H), 3.02 (td, J = 7.2, 14.0, 1H), 3.60 (dt, J = 7.2, 13.5, 2H), 3.75 (s, 3H), 3.80 (s, 3H), 6.0 (s,1H), 6.11 (broad s, 1H, NH), 6.71 (s, 1H), 6.82 (s, 1H), 7.50–7.25 (m, 8H), 7.70–7.67 (m, 2H); 13C-NMR: 167.8, 148.4, 147.6, 143.6, 134.4, 134.0, 131.4, 129.2, 128.5, 128.4, 127.3, 126.8, 126.5, 113.2, 111.6, 72.7, 55.9, 55.8, 41.3, 31.7. Anal. calcd. for C24H25NO4: C, 73.64; H, 6.44; N, 3.58. Found: C, 73.85; H, 6.23; N, 3.79.
N-(2-(Hydroxy(phenyl)methyl)-4,5-dimethoxyphenethyl)-2-phenylacetamide (4i): 1H-NMR: 1.90 (broad s, 1H, OH), 2.71–2.59 (m, 1H), 2.88 (ddd, J = 6.2, 7.4, 13.7, 1H), 3.54–3.25 (m, 2H), overlapped with 3.46 (s, 2H), 3.78 (s, 3H), 3.83 (s, 3H), 5.84 (t, J = 5.9, 1H, NH), 5.98 (d, J = 3.4, 1H), 6.59 (s, 1H), 6.82 (s, 1H), 7.17–7.14 (m, 2H), 7.37–7.25 (m, 8H); 13C-NMR: 171.4, 148.2, 147.6, 143.6, 134.8, 134.2, 129.4, 128.9, 128.7, 128.3, 127.2, 126.5, 113.1, 111.5, 72.4, 55.9, 55.8, 43.6, 40.7, 31.8. Anal. calcd. for C25H27NO4: C, 74.05; H, 6.71; N, 3.45. Found: C, 74.35; H, 6.97; N, 3.26.
Ethyl 2-(hydroxy(phenyl)methyl)-4,5-dimethoxyphenethylcarbamate (4j): 1H-NMR: 1.18 (t, J = 7.1, 3H), 2.70 (td, J = 7.4, 14.0, 1H), 2.89 (td, J = 6.9, 13.4, 1H), 3.07 (broad s, 1H, OH), 3.29 (dd, J = 8.7, 13.8, 2H), 3.76 (s, 3H), 3.85 (s, 3H), 4.04 (q, J = 7.1, 2H), 4.83 (t, J = 6.6, 1H, NH), 6.03 (s, 1H), 6.65 (s, 1H), 6.87 (s, 1H), 7.21–7.37 (m, 5H); 13C-NMR: 156.8, 148.3, 147.7, 142.6, 134.1, 128.7, 128.4, 128.3, 127.3, 126.6, 113.1, 111.2, 72.4, 60.8, 55.92, 55.89, 42.0, 32.6, 14.6. Anal. calcd. for C20H25NO5: C, 66.83; H, 7.01; N, 3.90. Found: C, 67.01; H, 7.26; N, 3.85.
N-(2-(Hydroxy(phenyl)methyl)-4,5-dimethoxyphenethyl)methanesulfonamide (4k): 1H-NMR: 1.48 (d, J = 6.4, 3H), 1.80 (broad s, 1H, OH), 2.74 (s, 3H), 2.79 (dd, J = 6.9, 13.8, 1H), 2.91 (td, J = 7.0, 14.0, 1H), 3.26 (dd, J = 5.9, 12.7, 2H), 3.76 (s, 3H), 3.86 (s, 3H), 5.12 (t, J = 5.7, 1H, NH), 6.00 (d, J = 1.8, 1H), 6.69 (s, 1H), 6.83 (s, 1H), 7.23–7.33 (m, 5H); 13C-NMR: 148.6, 147.7, 143.4, 134.0, 128.4, 127.5, 126.5, 113.1, 111.5, 72.7, 56.0, 55.9, 44.4, 39.9, 32.4. Anal. calcd. for C18H23NO5S: C, 59.16; H, 6.34; N, 3.83; S, 8.77. Found: C, 59.38; H, 6.15; N, 3.93; S, 8.95.
1-(2-(Hydroxy(phenyl)methyl)-4,5-dimethoxyphenethyl)-3-phenylurea (4l): 1H-NMR: 2.0 (broad s, 1H, OH), 2.66 (td, J = 6.7, 13.7, 1H), 2.88 (td, J = 7.0, 14.0, 1H), 3.34 (dq, J = 6.1, 13.3, 2H), 3.68 (s, 3H), 3.78 (s, 3H), 4.26 (s, 1H, NH), 5.53 (t, J = 6.1, 1H, NH), 6.02 (s, 1H), 6.62 (s, 1H), 6.77 (s, 1H), 6.97–7.04 (m, 1H), 7.17–7.31 (m, 9H); 13C-NMR: 156.4, 148.3, 147.5, 143.6, 138.6, 134.3, 129.3, 129.0, 128.3, 127.2, 126.4, 123.3, 120.4, 113.0, 111.5, 72.3, 55.9, 55.8, 41.5, 32.4. Anal. calcd. for C24H26N2O4: C, 70.92; H, 6.45; N, 6.89. Found: C, 71.23; H, 6.27; N, 6.95.
N-(2-(1-Hydroxy-2-phenylethyl)-4,5-dimethoxyphenethyl)acetamide (4m): 1H-NMR: 1.86 (s, 3H), 1.98 (broad s, 1H, OH), 2.65 (dt, J = 7.0, 14.0, 1H), 2.78 (dt, J = 7.0, 13.9, 1H), 3.06 (dd, J = 3.8, 6.6, 2H), 3.25 (dt, J = 7.0, 12.9, 1H), 3.44 (qd, J = 6.8, 6.9, 13.4, 1H), 3.86 (s, 3H), 3.89 (s, 3H), 5.01 (t, J = 6.7, 1H), 5.93(t, J = 4.9, 1H, NH), 6.60 (s, 1H), 7.05 (s, 1H), 7.17–7.30 (m, 5H); 13C-NMR: 170.4, 148.2, 147.8, 138.0, 133.8, 129.5, 128.5, 128.2, 126.6, 112.6, 109.6, 71.6, 55.9, 45.2, 40.7, 31.4, 23.0. Anal. calcd. for C20H25NO4: C, 69.95; H, 7.34; N, 4.08. Found: C, 70.17; H, 7.56; N, 3.89.
N-(2-(1-Hydroxy-2-phenylethyl)-4,5-dimethoxyphenethyl)benzamide (4n): 1H-NMR: 1.87 (broad s, 1H, OH), 2.65 (td, J = 4.7, 16.6, 1H), 2.88 (ddd, J = 6.3, 7.4, 13.6, 1H), 3.54–3.24 (m, 2H), overlapped with 3.45-3.47 (m, 2H), 3.78 (s, 3H), 3.83 (s, 3H), 5.83 (t, J = 5.7, 1H, NH), 5.98 (s, 1H), 6.59 (s, 1H), 6.82 (s, 1H), 7.17–7.14 (m, 2H), 7.37–7.22 (m, 8H); 13C-NMR: 171.4, 148.2, 147.6, 143.7, 134.8, 134.2, 129.4, 128.9, 128.7, 128.3, 127.2, 126.5, 113.1, 111.5, 72.4, 55.9, 55.8, 43.6, 40.7, 31.8. Anal. calcd. for C25H27NO4: C, 74.05; H, 6.71; N, 3.45. Found: C, 73.81; H, 6.43; N, 3.49.

3.3. Typical Procedure for the Preparation of Compounds 5

In a 100-mL round-bottomed flask fitted with a glass-rod, stirrer, reflux condenser and inlet for argon are placed magnesium turnings (0.36 g, 15 mmol) in dry diethyl ether (30 mL). The apparatus is flushed with argon. A slow stream of argon is introduced. About one-fifth of a solution of the corresponding halide (15 mmol) in dry ether (20 mL) is added to the vigorously stirred mixture. Reaction commences within 2–8 minutes and the remainder of the halide solution is then added steadily over about 12 minutes to the mixture. Stirring is continued for an additional 60 minutes followed by adding of solution of corresponding ketoamide 3 (3 mmol) in CH2Cl2 (10 mL). The reaction mixture is poured into water (the end of the reaction is proved with thin-layer chromatography) and extracted with CH2Cl2 (4 × 20 mL). If emulsion was formed, the saturated solution of ammonium chloride is added. The combined extracts were dried (Na2SO4) and concentrated. The corresponding product were isolated after column chromatography on silicagel with n-hexane:diethyl ether as eluent with 50–65% yields.
N-(2-(2-Hydroxypropan-2-yl)-4,5-dimethoxyphenethyl)acetamide (5a): 1H-NMR: 1.67 (s, 6H), 1.89 (s, 3H), 2.61 (broad s, 1H, OH), 3.14 (t, J = 7.1, 2H), 3.49 (dd, J = 12.4, 6.8, 2H), 3.87 (s, 6H), 5.31 (s, 1H, NH), 6.73 (s, 1H), 6.89 (s, 1H); 13C-NMR: 170.4, 147.7, 146.5, 138.0, 129.8, 114.7, 109.8, 56.0, 55.85, 42.1, 32.6, 29.4, 23.1. Anal. calcd. for C15H23NO4: C, 64.03; H, 8.24; N, 4.98. Found: C, 64.25; H, 8.05; N, 4.77.
N-(2-(2-Hydroxypropan-2-yl)-4,5-dimethoxyphenethyl)benzamide (5b): 1H-NMR: 1.71 (s, 6H), 2.74 (s, 1H, OH), 3.24 (t, J = 6.8, 2H), 3.69 (dd, J = 11.7, 6.9, 2H), 3.81 (s, 3H), 3.85 (s, 3H), 6.74 (s, 1H, NH), 6.86 (s, 1H), 7.26 (s, 1H), 7.33–7.42 (m, 3H), 7.69 (d, J = 1.6, 1H), 7.72 (t, J = 1.4, 1H); 13C-NMR: 167.6, 147.8, 146.6, 137.7, 134.6, 131.1, 129.98, 128.3, 126.9, 114.7, 109.8, 56.1, 55.8, 42.6, 32.7, 32.2. Anal. calcd. for C20H25NO4: C, 69.95; H, 7.34; N, 4.08. Found: C, 69.64; H, 7.33; N, 4.17.
N-(2-(2-Hydroxypropan-2-yl)-4,5-dimethoxyphenethyl)-2-phenylacetamide (5c): 1H-NMR: 1.58 (s, 6H), 1.88 (s, 1H, OH), 3.08 (t, J = 6.9, 2H), 3.49-3.53 (m, 4H), 3.85 (s, 3H), 3.88 (s, 3H), 6.68 (s, 1H, NH), 6.81 (s, 1H), 7.14 (s, 1H), 7.15–7.18 (m, 2H), 7.29–7.33 (m, 3H); 13C-NMR: 171.3, 147.7, 146.4, 137.9, 135.1, 129.7, 128.8, 127.1, 114.5, 109.6, 56.1, 55.8, 43.7, 42.1, 32.3, 31.9. Anal. calcd. for C21H27NO4: C, 70.56; H, 7.61; N, 3.92. Found: C, 70.34; H, 7.56; N, 4.22.
N-(2-(2-Hydroxy-1-phenylpropan-2-yl)-4,5-dimethoxyphenethyl)benzamide (5n): 1H-NMR: 1.65 (s, 3H), 2.65 (s, 1H, OH), 3.03 (td, J = 5.5, 13.2, 1H), 3.12(d, J = 13.2, 1H), 3.21 (d, J = 13.2, 1H), 3.50 (ddd, J = 6.2, 8.6, 14.4, 1H), 3.70 (tt, J = 4.5, 8.9, 2H), 3.78 (s, 3H), 3.83 (s, 3H), 6.70 (s, 1H), 6.76 (s, 1H), 7.08 (dd, J = 1.6, 8.2, 2H), 7.24-7.28 (m, 3H), 7.33 (t, J = 7.7, 2H) 7.41 (t, J = 7.4, 1H), 7.63 (t, J = 4.7, 1H, NH), 7.71 (dd, J = 1.1, 8.4, 2H); 13C-NMR: 167.5, 147.9, 146.5, 136.7, 136.3, 134.6, 131.1, 130.8, 130.3, 128.3, 128.2, 128.19, 127.0, 126.9, 114.5, 110.4, 76.2, 56.1, 55.7, 50.5, 42.8, 31.9, 30.1. Anal. calcd. for C26H29NO4: C, 74.44; H, 6.97; N, 3.34. Found: C, 74.25; H, 6.77; N, 3.53.
N-(2-(2-Hydroxybutan-2-yl)-4,5-dimethoxyphenethyl)benzamide (5p): 1H-NMR: 0.92 (t, J = 7.4, 3H), 1.71 (s, 3H), 1.76 (ddd, J = 0.9, 2.0, 6.6, 2H), 2.90 (dt, J = 4.6, 7.0, 2H), 3.70 (ddd, J = 5.7, 7.1, 19.5, 2H), 3.85 (s, 3H), 3.90 (s, 3H), 6.22 (broad s, 1H, NH), 6.64 (s, 1H), 6.75 (s, 1H), 7.42–7.49 (m, 3H), 7.70–7.79 (m, 2H); 13C-NMR: 167.5, 147.6, 138.6, 136.3, 131.4, 130.1, 128.6, 128.4, 126.8, 124.4, 112.5, 110.8, 106.0, 63.9, 56.2, 55.8, 41.4, 32.3, 18.8, 12.4. Anal. calcd. for C21H27NO4: C, 70.56; H, 7.61; N, 3.92. Found: C, 70.26; H, 7.43; N, 4.13.
N-(2-(1-Hydroxy-1-phenylethyl)-4,5-dimethoxyphenethyl)benzamide (5s): 1H-NMR: 1.98 (s, 3H), 2.68 (t, J = 6.9, 2H), 2.79 (dd, J = 7.3, 13.8, 1H), 3.27 (dt, J = 6.2, 13.4, 1H), 3.84 (s, 3H), 3.92 (s, 3H), 5.80 (d, J = 1.3,1H, NH) 6.77 (s, 1H), 7.15 (s, 1H), 7.24–7.48 (m, 10H); 13C-NMR: 167.6, 149.3, 148.8, 147.4, 146.3, 134.6, 131.4, 126.5, 125.3, 115.5, 114.6, 113.8, 112.7, 110.9, 56.2, 55.9, 41.4, 40.7, 33.6. Anal. calcd. for C25H27NO4: C, 74.05; H, 6.71; N, 3.45. Found: C, 74.32; H, 6.97; N, 3.37.
N-(2-(1-Hydroxy-1-phenylpropyl)-4,5-dimethoxyphenethyl)methanesulfonamide (5t): 1H-NMR: 0.90 (t, J = 7.3, 3H), 2.30 (dq, J = 7.3, 13.8, 2H), 2.53 (broad s, 1H, OH), 2.67 (s, 3H), 2.73 (dd, J = 4.9, 9.0, 2H), 2.86 (td, J = 5.9, 17.8, 1H), 2.94–3.04 (m, 1H), 3.88 (s, 3H), 3.94 (s, 3H), 4.60 (t, J = 5.3, 1H, NH), 6.66 (s, 1H), 7.18 (s, 1H), 7.20–7.32 (m, 5H); 13C-NMR: 148.2, 147.2, 146.5, 137.1, 130.4, 127.9, 126.7, 125.9, 114.7, 111.1, 105.9, 78.6, 56.2, 55.9, 44.4, 39.7, 36.2, 32.7, 8.1. Anal. calcd. for C20H27NO5S: C, 61.05; H, 6.92; N, 3.56; S, 8.15. Found: C, 60.81; H, 6.64; N, 3.65; S, 7.83.

3.4. Cyclization of 4 and 5 to the Corresponding Isoquinolines 6 and 7

To solution of the corresponding compound 4 or 5 (1 mmol) in dichloromethane (15 mL) a catalytic amount of p-toluensulfonic acid (PTSA) was added. The solution was stirred 30 min at room temperature, then the solution was filtered on a short column with neutral Al2O3. The products 6 or 7, after evaporation of the solvent, were obtained with 88–90% yields. When the substituent at the C-1 is ethyl or benzyl, the styrene products 8 were formed predominantly (~60%) than expected cyclic 1,1-disubtituted product 7 (~30%).
1-(6,7-Dimethoxy-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (6а): known compound [49,50,51].
(6,7-Dimethoxy-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)(phenyl)methanone (6b): 1H-NMR (600 MHz): 1.60 (d, J = 6.7, 3H), 2.63 (d, J = 16.7, 1H), 2.94 (ddd, J = 5.3, 12.0, 17.3, 1H), 3.16 (td, J = 14.0, 30.6, 1H), 3.44 (dt, J = 3.2, 13.1, 1H), 3.88 (s, 6H), 5.72 (q, J = 5.7, 1H), 6.61 (s, 1H), 6.69 (s, 1H), 7.43–7.45 (m, 5H); 13C-NMR: 170.2, 147.9, 147.7, 136.7, 136.6, 129.5, 128.6, 126.6, 111.2, 109.8, 56.0, 55.9, 53.4, 40.9, 29.2, 21.5. Anal. calcd. for C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found: C, 72.95; H, 6.98; N, 4.45.
1-(6,7-Dimethoxy-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-phenylethanone (6c): 1H-NMR (600 MHz): 1.40 (d, J = 6.8, 1H), 1.46 (d, J = 6.8, 3H), 2.52–2.60 (m, 2H), 3.40 (ddd, J = 5.0, 10.5, 13.5, 1H), 3.83 (d, J = 4.3, 2H), 3.85 (s, 3H), 3.87 (s, 3H), 5.63 (q, J = 6.8, 1H), 6.53 (s, 1H), 6.62 (s, 1H), 7.23–7.36 (m, 5H); 13C-NMR: 169.3, 147.9, 147.5, 135.2, 130.4, 128.9, 128.7, 126.8, 111.0, 109.8, 56.0, 55.9, 52.2, 41.8, 40.0, 28.8, 21.4. Anal. calcd. for C20H23NO3: C, 73.82; H, 7.12; N, 4.30. Found: C, 73.57; H, 7.31; N, 4.34.
Ethyl 6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (6d): known compound [52,53,54,55].
6,7-dimethoxy-1-methyl-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (6e): known compound [56].
6,7-dimethoxy-1-methyl-N-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (6f): known compound [57].
1-(6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (6g): known compound [58,59,60].
(6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)(phenyl)methanone (6h): known compound [58,59,60].
1-(6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-phenylethanone (6i): 1H-NMR (600 MHz): 2.61 (dd, J = 4.1, 7.7, 2H), 3.33 (td, J = 8.7, 14.3, 1H), 3.78 (s, 3H), overlapped with 3.74–3.79 (m, 1H), 3.83 (d, J = 2.0, 2H), 3.89 (s, 3H), 6.56 (s, 1H), 6.62 (s, 1H), 6.95 (s, 1H), 7.22–7.34 (m, 10H); 13C-NMR: 169.99, 147.6, 142.7, 142.5, 135.1, 128.8, 128.7, 128.2, 127.4, 126.7, 126.3, 111.4, 111.0, 92.2, 55.96, 55.88, 54.7, 41.4, 39.8, 28.4. Anal. calcd. for C25H25NO3: C, 77.49; H, 6.50; N, 3.61; Found: C, 77.68; H, 6.75; N, 3.56.
Ethyl 6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (6j): known compound [61,62,63].
6,7-Dimethoxy-2-(methylsulfonyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (6k): 1H-NMR: 2.64 (s, 3H), 2.76 (ddd, J = 1.7, 4.5, 16.8, 1H), 3.09 (ddd, J = 6.3, 11.7, 16.3, 1H), 3.29 (ddd, J = 4.6, 11.8, 13.6, 1H), 3.77 (s, 3H), 3.82-3.91 (m, 1H), 3.92 (s, 3H), 6.02 (s, 1H), 6.48 (s, 1H), 6.71 (s, 1H), 7.27–7.36 (m, 5H); 13C-NMR: 148.5, 147.8, 140.9, 128.9, 128.5, 128.0, 125.8, 125.7, 111.5, 110.9, 58.7, 56.0, 55.9, 39.6, 38.5, 21.1. Anal. calcd. for C18H21NO4S: C, 62.23; H, 6.09; N, 4.03; S, 9.23. Found: C, 62.03; H, 6.27; N, 4.09; S, 9.15.
6,7-Dimethoxy-N,1-diphenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (6l): 1H-NMR (600 MHz): 1.56 (s, 1H), 2.71 (d, J = 16.4, 1H), 2.87 (dd, J = 7.3, 15.9, 1H), 3.51 (ddd, J = 2.9, 6.7, 11.7, 1H), 3.71 (s, 3H), 3.81 (s, 3H), 6.35 (s, 1H), 6.45 (broad s, 1H, NH), 6.55 (s, 1H), 6.61 (s, 1H), 6.95 (t, J = 7.2, 1H), 7.18–7.23 (m, 4H), 7.22–7.27 (m, 5H); 13C-NMR: 154.9, 148.1, 147.6, 142.7, 139.1, 128.9, 128.6, 127.9, 127.8, 127.6, 126.9, 123.1, 120.0, 111.2, 111.1, 57.4, 56.1, 56.0, 40.0, 28.1. Anal. calcd. for C24H24N2O3: C, 74.21; H, 6.23; N, 7.21. Found: C, 74.43; H, 6.45; N, 7.13.
1-(1-Benzyl-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (6m): 1H-NMR: 1.63 (s, 3H), 2.84 (ddd, J = 5.6, 10.1, 14.8, 2H), 3.09–3.17 (m, 2H), 3.50 (ddd, J = 3.4, 7.8, 10.8, 1H), 3.69 (td, J = 5.6, 12.9, 1H), 3.87 (s, 3H), 3.89 (s, 3H), 5.68 (dd, J = 5.3, 8.4, 1H), 6.14 (s, 1H), 6.48 (s, 1H), 7.17–7.27 (m, 5H); 13C-NMR: 169.5, 148.2, 147.3, 138.2, 129.6, 128.7, 128.2, 126.7, 125.5, 110.9, 110.1, 59.3, 56.0, 55.8, 43.2, 35.1, 28.6, 22.0. Anal. calcd. for C20H23NO3: C, 73.82; H, 7.12; N, 4.30. Found: C, 73.99; H, 7.05; N, 4.25.
(1-Benzyl-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)(phenyl)methanone (6n): known compound [57].
1-(6,7-Dimethoxy-1,1-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (7a): 1H-NMR: 1.82 (s, 6H), 2.21 (s, 3H), 2.79 (t, J = 5.5, 2H), 3.56 (dt, J = 5.5, 3.8, 2H), 3.87 (s, 3H), 3.89 (s, 3H), 6.57 (s, 1H), 6.77 (s, 1H); 13C-NMR: 170.3, 147.9, 147.1, 137.0, 126.3, 110.5, 109.6, 59.85, 56.1, 55.8, 44.1, 30.4, 27.99, 25.6. Anal. calcd. for C15H21NO3: C, 68.42; H, 8.04; N, 5.32. Found: C, 68.65; H, 8.18; N, 5.14.
(6,7-Dimethoxy-1,1-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)(phenyl)methanone (7b): 1H-NMR: 1.96 (s, 6H), 2.80 (t, J = 5.5, 2H), 3.52 (dt, J = 5.5, 3.5, 2H), 3.89 (s, 3H), 3.92 (s, 3H), 6.59 (s, 1H), 6.84 (s, 1H), 7.42–7.46 (m, 3H), 7.48–7.52 (m, 2H); 13C-NMR: 172.6, 147.9, 147.2, 138.9, 136.8, 129.6, 128.5, 126.7, 126.1, 110.8, 109.7, 59.9, 56.1, 55.9, 45.3, 30.4, 27.7; Anal. calcd. for C20H23NO3: C, 73.82; H, 7.12; N, 4.30. Found: C, 73.87; H, 7.05; N, 4.57.
1-(6,7-Dimethoxy-1,1-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-phenylethanone (7c): 1H-NMR: 1.84 (s, 6H), 2.49 (t, J = 5.3, 2H), 3.47 (dt, J = 4.8, 6.0, 2H), 3.82 (s, 3H), overlapped with 3.83 (s, 2Н), 3.86 (s, 3H), 6.47 (s, 1H), 6.75 (s, 1H), 7.23–7.27 (m, 2H), 7.30–7.33 (m, 3H); 13C-NMR: 170.9, 147.8, 147.1, 136.8, 135.6, 128.6, 128.4, 126.6, 126.3, 110.5, 109.6, 60.1, 56.1, 55.8, 44.8, 43.8, 30.1, 27.9; Anal. calcd. for C21H25NO3: C, 74.31; H, 7.42; N, 4.13. Found: C, 74.26; H, 7.38; N, 4.20.
Ethyl 6,7-dimethoxy-1,1-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (7d): 1H-NMR: 1.32 (dd, J = 6.4, 13.5, 3H), 1.79 (s, 6H), 2.75 (t, J = 5.5, 2H), 3.73–3.77 (m, 2H), 3.88 (s, 3H), 3.89 (s, 3H), 4.19 (q, J = 7.12, 7.09, 2H), 6.57 (s, 1H), 6.78 (s, 1H); 13C-NMR: 181.6, 147.7, 147.1, 136.5, 127.0, 110.6, 109.8, 60.8, 58.6, 56.1, 55.8, 47.8, 30.2, 28.8, 14.6. Anal. calcd. for C16H23NO4: C, 65.51; H, 7.90; N, 4.77. Found: C, 65.84; H, 7.76; N, 4.80.
6,7-Dimethoxy-1,1-dimethyl-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (7e): 1H-NMR: 1.86 (s, 6H), 2.81 (dd, J = 5.0, 6.0, 2H), 2.98 (s, 3H), 3.67–3.62 (m, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 6.54 (s, 1H), 6.71 (s, 1H); 13C-NMR: 147.8, 147.5, 135.6, 125.9, 110.9, 109.3, 61.4, 56.2, 55.8, 43.0, 42.6, 30.4, 30.0. Anal. calcd. for C14H21NO4S: C, 56.16; H, 7.07; N, 4.68; S, 10.71. Found: C, 56.36; H, 7.18; N, 4.63; S, 10.97.
(1-Benzyl-6,7-dimethoxy-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)(phenyl)methanone (7n): 1H-NMR: 2.09 (s, 3H), 2.27 (ddd, J = 2.7, 4.8, 15.2, 1H), 3.07 (ddd, J = 8.0, 12.6, 22.8, 1H), 3.21 (td, J = 4.1, 13.3, 1H), 3.88 (s, 3H), 3.97 (s, 3H), 4.56 (d, J = 13.3, 1H), 6.42 (s, 1H), 6.68 (dd, J = 1.5, 8.6, 2H), 7.00 (s, 1H), 7.05 (t, J = 7.5, 2H), 7.11–7.13 (m, 1H), 7.24 (d, J = 5.6, 2H), 7.35–7.38 (m, 3H); 13C-NMR: 172.4, 147.9, 147.3, 139.1, 137.8, 133.7, 130.1, 129.3, 129.0, 128.5, 127.5, 127.4, 126.4, 126.2, 126.15, 110.2, 109.8, 64.2, 56.3, 56.2, 45.9, 45.3, 29.7, 26.4. Anal. calcd. for C26H27NO3: C, 77.78; H, 6.78; N, 3.49. Found: C, 77.53; H, 6.87; N, 3.52.
1-(1-Ethyl-6,7-dimethoxy-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (7o): 1H-NMR: 0.55 (t, J = 7.4, 3H), 1.65 (dt, J = 7.3, 14.6, 1H), 1.78 (s, 3H), 2.24–2.26 (m, 1H), 2.70 (ddd, J = 3.4, 5.3, 15.6, 1H), 2.86 (ddd, J = 4.9, 10.1, 13.0, 1H), 3.29 (dd, J = 7.4, 14.1, 1H), 3.42 (ddd, J = 3.3, 9.4, 13.0, 1H), 3.89 (s, 6H), 6.58 (s, 1H), 6.76 (s, 1H); 13C-NMR: 185.6, 148.0, 147.0, 134.6, 128.1, 110.2, 109.2, 63.9, 56.1, 55.8, 44.7, 33.4, 26.7, 25.5, 8.5. Anal. calcd. for C16H23NO3: C, 69.29; H, 8.36; N, 5.05. Found: C, 69.13; H, 8.48; N, 5.12.
(1-Ethyl-6,7-dimethoxy-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)(phenyl)methanone (7p): 1H-NMR: 0.66 (t, J = 7.3, 3H), 1.77 (dd, J = 7.2, 14.1, 1H), 1.93 (s, 3H), 2.60 (ddd, J = 3.1, 4.0, 15.3, 1H), 2.94 (ddd, J = 3.6, 10.5, 14.5, 1H), 3.31 (ddd, J = 2.8, 10.5, 13.3, 1H), 3.43 (dd, J = 7.2, 14.1, 1H), 3.77 (td, J = 4.0, 13.3, 1H), 3.90 (s, 3H), 3.93 (s, 3H), 6.59 (s, 1H), 6.81 (s, 1H), 7.43–7.51 (m, 5H); 13C-NMR: 172.0, 148.0, 147.2, 139.0, 129.4, 128.5, 128.0, 126.6, 110.5, 109.3, 63.8, 56.1, 55.8, 45.8, 33.0, 30.3, 26.4, 8.5. Anal. calcd. for C21H25NO3: C, 74.31; H, 7.42; N, 4.13. Found: C, 74.11; H, 7.64; N, 4.03.
1-Ethyl-6,7-dimethoxy-1-methyl-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (7r): 1H-NMR: 0.72 (t, J = 7.3, 3H), 1.77 (dd, J = 8.1, 15.4, 1H), 1.84 (s, 3H), 2.74–2.80 (m, 2H), 2.83-2.89 (m, 1H), 2.99 (s, 3H), 3.42 (ddd, J = 3.4, 8.8, 12.3, 1H), 3.72 (ddd, J = 4.1, 5.7, 12.4, 1H), 3.88 (s, 6H), 6.56 (s, 1H), 6.69 (s, 1H); 13C-NMR: 148.0, 147.4, 133.4, 127.6, 110.6, 108.9, 65.5, 56.2, 55.8, 43.6, 41.2, 36.2, 30.2, 28.2, 8.6. Anal. calcd. for C15H23NO4S: C, 57.48; H, 7.40; N, 4.47; S, 10.23. Found: C, 57.24; H, 7.62; N, 4.54; S, 10.35.
(6,7-Dimethoxy-1-methyl-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)(phenyl)methanone (7s): 1H-NMR: 2.26 (s, 3H), 2.85 (ddd, J = 3.1, 5.4, 15.4, 1H), 3.21 (ddd, J = 4.1, 9.4, 14.7, 1H), 3.59–3.69 (m, 1H), overlapped with 3.64 (s, 3H), 3.88 (s, 3H), 3.97 (ddd, J = 4.3, 5.2, 13.3, 1H), 6.28 (s, 1H), 6.61 (s, 1H), 7.39-7.45 (m, 5H), 7.47-7.51 (m, 5H). Anal. calcd. for C25H25NO3: C, 77.49; H, 6.50; N, 3.61. Found: C, 77.14; H, 6.73; N, 3.65.
1-Ethyl-6,7-dimethoxy-2-(methylsulfonyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (7t): 1H-NMR: 0.80 (t, J = 7.2, 3H), 1.90 (s, 3H), 1.98 (dd, J = 6.6, 13.8, 1H), 2.82 (td, J = 2.7, 15.4, 1H), 3.14 (ddd, J = 4.1, 11.6, 15.6, 1H), 3.30 (dt, J = 2.4, 11.1, 11.3, 1H), 3.59 (s, 3H), 3.64 (dd, J = 7.3, 13.8, 1H), 3.91 (s, 3H), 4.05 (td, J = 3.8, 7.1, 1H), 6.09 (s, 1H), 6.61 (s, 1H), 7.29–7.40 (m, 3H), 7.48–7.53 (m, 2H); 13C-NMR: 148.0, 147.5, 144.0, 133.3, 128.9, 128.2, 128.1, 127.8, 111.2, 109.5, 69.1, 56.0, 55.8, 43.2, 37.1, 34.5, 30.0, 6.3. Anal. calcd. for C20H25NO4S: C, 63.97; H, 6.71; N, 3.73; S, 8.54. Found: C, 64.41; H, 6.88; N, 3.76; S, 8.14.
N-(2-(but-2-en-2-yl)-4,5-dimethoxyphenethyl)benzamide (8g): 1H-NMR: 1.76 (ddd, J = 0.9, 2.0, 6.6, 1H), 1.96 (td, J = 1.2, 2.2, 1H), 2.90 (dt, J = 4.5, 7.01, 2H), 3.29 (tdd, J = 6.2, 12.7, 19.5, 2H), 3.85 (s, 3H), 3.89 (s, 3H), 5.41 (dq, J = 1.45, 6.7, 1H), 6.22 (broad s, 1H, NH), 6.40 (s, 1H), 6.75 (s, 1H), 7.42–7.49 (m, 3H), 7.71–7.75 (m, 2H); 13C-NMR: 167.5, 147.9, 147.2, 147.1, 138.6, 136.3, 131.4, 128.6, 128.5, 127.0, 124.4, 112.5, 112.4, 56.2, 55.9, 41.4, 32.4, 18.8, 13.9. Anal. calcd. for C21H25NO3: C, 74.31; H, 7.42; N, 4.13. Found: C, 74.12; H, 7.54; N, 4.15.
N-(4,5-dimethoxy-2-(1-phenylprop-1-enyl)phenethyl)benzamide (8n): 1H-NMR: 2.22 (d, J = 1.1, 3H), 2.95 (t, J = 7.1, 2H), 3.70 (dd, J = 6.9, 13.1, 2H), 3.84 (s, 3H), 3.89 (s, 3H), 6.23 (t, J = 4.7, 1H, NH), 6.39 (s, 1H), 6.73 (s, 1H), 6.78 (s, 1H), 7.34–7.39 (m, 7H, Ar), 7.44–7.47 (m, 1H, Ar), 7.68 (dd, J = 1.2, 8.4, 2H); 13C-NMR: 167.4, 147.9, 147.3, 138.4, 137.6, 131.4, 129.9, 128.9, 128.5, 128.3, 128.2, 127.5, 126.8, 126.7, 126. 66, 112.5, 111.8, 56.0, 55.8, 41.4, 32.5, 21.1. Anal. calcd. for C26H27NO3: C, 77.78; H, 6.78; N, 3.49. Found: C, 77.85; H, 6.89; N, 3.55.
N-(4,5-dimethoxy-2-(1-phenylvinyl)phenethyl)benzamide (8s): 1H-NMR: 2.69 (t, J = 7.2, 2H), 3.52 (dd, J = 7.0, 12.9, 2H), 3.88 (s, 3H), 3.89 (s, 3H), 5.25 (d, J = 1.3, 1H), 5.81 (d, J = 1.4, 1H), 6.00 (t, J = 6.1, 1H, NH), 6.80 (s, 1H), 6.81 (s, 1H), 7.28–7.31 (m, 4H), 7.38–7.50 (m, 4H), 7.65–7.69 (m, 2H); 13C-NMR: 167.3, 148.8, 148.5, 147.3, 140.7, 134.6, 133.8, 131.3, 129.0, 128.5, 127.9, 126.7, 126.5, 115.5, 114.6, 113.8, 112.7, 56.0, 55.9, 40.8, 32.7. Anal. calcd. for C25H25NO3: C, 77.49; H, 6.50; N, 3.61. Found: C, 77.64; H, 6.65; N, 3.55.
N-(4,5-dimethoxy-2-(1-phenylprop-1-enyl)phenethyl)methanesulfonamide (8t): 1H-NMR: 0.81 (t, J = 7.3, 3H), 2.09 (ddd, J = 6.2, 8.6, 12.6, 2H), 2.97 (s, 3H), 3.23 (td, J = 1.7, 7.1, 2H), 3.46–3.50 (m, 1H), 3.86 (s, 3H), 3.88 (s, 3H), 6.43 (s, 1H), 6.71 (s, 1H), 6.82–6.86 (m, 2H), 7.05-7.13 (m, 3H); 13C-NMR: 147.9, 147.3, 139.1, 137.8, 133.7, 130.1, 129.3, 129.0, 128.5, 127.4, 126.4, 126.2, 110.2, 109.8, 56.2, 55.9, 45.9, 45.3, 29.7, 26.4. Anal. calcd. for C20H25NO4S: C, 63.97; H, 6.71; N, 3.73; S, 8.54. Found: C, 63.76; H, 6.81; N, 3.77; S, 8.24.

3.5. Estimation of Contractile Activity of Some of the Newly Synthesized Compounds

3.5.1. Collection and Preparation of Tissue Samples

Guinea-pigs (350 ± 50g) were used. Whole mount muscle preparations without mucosa were obtained from gastric corpus. The tissue was pinned flat in a dissecting dish containing preparation solution containing (mmol/L) Na+ - 143; K+ - 5.84; Ca2+ - 3.7 and preparations were cut longitudinal muscle fibres with a final size of (13.0 ± 1.5−1.0 ± 1.5) mm. Tissue samples were immediately rinsed with cooled (4 °C) preparation solution. The muscle preparations were suspended in fort individual organ baths containing 15 mL modified Krebs’ solution (KS) containing (mmol/L) Na+ - 143, K+ - 5.84, Ca2+ - 2.5, Mg2+ - 1.19, Cl− - 133, HCO3− - 16.7, H2PO4− - 1.2 and 11.5 glucose (35.5 ± 0.25 °C) each and constantly oxygenated with 95% O2 and 5% CO2. The preparations were connected to an isometric force transducer (TRI 201, LSi LETICA; Pnlab s.l., Barcelona, Spain). Preparations were allocated to the organ baths in random manner and were allowed an equilibration period of 1 h. Muscle tension was preset to 7 mN g in one step during the equilibration time. The mechanical activity was amplified with 4-channels tensiometrical interface system for registration and investigation of spontaneous muscle contractility of the muscle strips.

3.5.2. Estimation of SM Contractile Activity after Applications of Newly Synthesized Compounds

Preparations from 3 to 5 guinea-pigs were used for each experiment of studying of effect of application of isoquinoline derivatives. Basal tone (BT), frequency, mean amplitude (Amean) and area under the curve (AUC) were analysed after the equilibration time for a 5-min period. These values were defined as predrug (baseline period) and were used for further comparative analysis.
Again, at the end of each trial, the organ baths were flushed and 1 × 10−5 M acetylcholine was added to test the ability of the preparations to exert a contractile response after activation of cholinergic receptors. For each trial, four preparations from the same animal were used and compounds were assigned to the organ baths in random order.
The signal digitalisations ware achieved by 13 bit analogue to digital converter based on microcontroller. A logical level synchronization was developed by special controller for parallel PC port communication. The calibration curve was used to define the range of application of registration system 0–20 mN.
Special Visual-Basic program was assembled to visualization of spontaneous smooth muscle activity with options to dynamically alteration of amplification, offset value and printing ability of smooth-muscle parameter. It is possible to build in the first deviation of the signals and saving of incoming data in 4 dimensional matrixes with appropriated format to statistical analysis.

3.5.3. Parameters, Data Analysis and Statistics

The following parameters were analysed to describe contractility parameters for each application: BT, Amean, AUC and frequency. Basal tone of the muscle has been measured because an increase in this parameter can be independent of Amean of contractions or frequency of contractions. In addition to an increase or decrease in BT, changes in frequency of contractions or Amean indicate changes in contractility due to the drugs used. The variables were calculated by using the software ChartTM included in the PowerLab from ADInstruments Ltd, Australia. All results were expressed as percentage of the corresponding predrug measurement.
Statistical analysis was performed using Statistica 4.5 (StaSoft, Inc. Microsoft), SPSS Inc., Chicago, IL, USA, Excel VB for applications end PraphPad. Data were subjected to descriptive and comparative analyses.
Data of are presented as mean and standard error (SEM), and 25 and 75% percentiles. Wilcoxon signed rank test was used to compare predrug between solvent and drug. In case of no significant difference in predrug between specimens used for solvent and drug, further calculations were performed. Differences within the results were analysed by the Friedman test. If Friedman analysis revealed significant differences for compound and the corresponding control, Wilcoxon signed rank test was used.

4. Conclusions

In conclusion, new isoquinoline derivatives were synthesized, as type of compounds found in nature and among bioactive compounds of interest. We have developed a convenient method for their synthesis by interaction of ketoamides with organomagnesium compounds, followed by cyclization in acidic medium with a catalytic amount of PTSA. A variety of substituents at the C-1 in the isoquinoline skeleton can be readily introduced. The estimation of contractile activity against smooth muscle preparations showed that some of the obtained compounds, especially 1,1-dialkyl 1,2,3,4-tetrahydroisoquinolines with sulfonamide substitutent possess the most pronounced effect.

Acknowledgments

We acknowledge financial support from the National Fund for Scientific Research DO-02-195.

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  • Sample Availability: Samples of the compounds are available from the authors.

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Ivanov, I.; Nikolova, S.; Aladjov, D.; Stefanova, I.; Zagorchev, P. Synthesis and Contractile Activity of Substituted 1,2,3,4-Tetrahydroisoquinolines. Molecules 2011, 16, 7019-7042. https://doi.org/10.3390/molecules16087019

AMA Style

Ivanov I, Nikolova S, Aladjov D, Stefanova I, Zagorchev P. Synthesis and Contractile Activity of Substituted 1,2,3,4-Tetrahydroisoquinolines. Molecules. 2011; 16(8):7019-7042. https://doi.org/10.3390/molecules16087019

Chicago/Turabian Style

Ivanov, Iliyan, Stoyanka Nikolova, Dimo Aladjov, Iliyana Stefanova, and Plamen Zagorchev. 2011. "Synthesis and Contractile Activity of Substituted 1,2,3,4-Tetrahydroisoquinolines" Molecules 16, no. 8: 7019-7042. https://doi.org/10.3390/molecules16087019

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