Synthesis and contractile activity of substituted 1,2,3,4- tetrahydroisoquinolines

Article abstract of DOI:10.3390/molecules16087019

A series of different 1-monosubstituted and 1,1-disubstituted 1,2,3,4-tetrahydroisoquinolines was synthesized in high yields from different ketoamides. We have developed a convenient method for the synthesis of disubstituted derivatives by interaction of

Full text of DOI:10.3390/molecules16087019

Molecules 2011, 16, 7019-7042; doi:10.3390/molecules16087019
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and Contractile Activity of Substituted
1,2,3,4-Tetrahydroisoquinolines
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; E-Mails: ivanov@uni-plovdiv.bg (I.I.);
plamenz@gbg.bg (P.Z.); Tel.: +359-32-261-349; Fax: +359-32-261-403.
Received: 22 July 2011; in revised form: 10 August 2011 / Accepted: 11 August 2011 /
Published: 16 August 2011
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.
Keywords: Grignard reagent; tetrahydroisoquinolines; contractile activity
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) [3-5], the esteinascidine family
(ET743) [6-9] and spiro-benzoisoquinoline alkaloids (parfumine) [10,11]. Within the series of

Molecules 2011, 16
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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 [17-20]. 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 [28-30]. 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 [34-38]. 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-β-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 β-keto esters, followed by acid-catalyzed ring closure of resulting
enamines to corresponding 1,1-disubtituted indoles.

Molecules 2011, 16
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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 [43-47]. 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.
Scheme 1. Retrosynthetic scheme for the synthesis of both 1-monosubstituted and
1,1-disubstituted 1,2,3,4-tetrahydroisoquinolines.
MeO
MeO
MeO
MeO
N
R1
N
R1
7
6
R2
R3
R2
MeO
NH R1
O
MeO
3
R2
MeO
MeO
NH2
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-β-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 2011, 16
7022
Scheme 2. Synthesis of starting ketoamides.
R2COOH
MeO
NH R1
MeO
NH R1
or
(R2CO)2O (2)
O
MeO
PPA
MeO
3
1
R2
Table 1. Reaction conditions and yields for starting ketoamides 3.
3
a
b
c
R1
R2
CH3
Reaction conditions
2 h, 80 °С
2 h, 80 °С
2 h, 80 °С
3 h, 80 °С
2 h, 80 °С
2 h, 60 °С
2 h, 80 °С
2 h, 80 °С
4 h, 60 °С
3 h, 80 °С
3h, 80 °C
mp, °C
124–125
147–148
135–137
90–90.5
140–141
118–121
212–213
117–121
108–111
97–98
Yield [%]
СОCH3
92
80
79
95
75
75
87
85
89
89
83
76
62
82
COC6H5
CH3
COCH2C6H5
COOC2H5
SO2CH3
CH3
d
e
CH3
CH3
f
CONHC6H5
СОCH3
CH3
g
h
i
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH2C6H5
CH2C6H5
COC6H5
COCH2C6H5
COOC2H5
SO2CH3
j
k
l
84–86
CONHC6H5
СОCH3
4 h, 60 °С
20 h, 60 °С
20 h, 60 °С
128–131
188–189
141–141.5
m
n
COC6H5
Scheme 3. Synthesis of 1-substituted and 1,1-disubstituted-1,2,3,4-tetrahydroisoquinolines.
MeO
MeO
NH R1
O
3
R2
R3MgX
dry ether
NaBH4
MeO
MeO
NH R1
MeO
NH R1
OH
OH
R3
MeO
5
4
R2
PTSA
R2
PTSA
MeO
MeO
MeO
MeO
N
R1
N
R1
7
6
R2
R3
R2

Molecules 2011, 16
7023
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 2. Synthesis of hydroxyamides 4.
4
a
b
c
R1
R2
CH3
Yield [%]
mp, °C
108–110
109–110
oil
СОCH3
95
94
92
92
90
91
94
90
91
91
90
90
95
91
COC6H5
CH3
COCH2C6H5
COOC2H5
SO2CH3
CH3
d
e
CH3
85–87
oil
CH3
f
CONHC6H5
СОCH3
CH3
147–150
133–135
58–60
oil
g
h
i
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH2C6H5
CH2C6H5
COC6H5
COCH2C6H5
COOC2H5
SO2CH3
j
92–95
oil
k
l
CONHC6H5
СОCH3
73–75
oil
m
n
COC6H5
117–118
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 3. Reaction of ketoamides with Grignard reagents.
5
a
b
c
d
e
n
o
p
r
s
R1
R2
CH3
R3
Yield [%]
mp, °C
СОCH3
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
C2H5
C2H5
C6H5
C2H5
52
50
50
- *
- *
50
- *
65
- *
50
51
oil
COC6H5
COCH2C6H5
COOC2H5
SO2CH3
COC6H5
СОCH3
CH3
160–162
CH3
oil
CH3
-
CH3
-
48–50
-
CH2C6H5
CH3
COC6H5
SO2CH3
COC6H5
SO2CH3
CH3
131–135
-
CH3
CH3
96–98
131–134
t
C6H5
* compounds were directly cyclized.

Molecules 2011, 16
7024
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 4. Synthesis of 1-substituted 1,2,3,4-tetrahydroisoquinolines.
6
a
b
c
R1
R2
CH3
Yield [%]
mp, °C
97–98
СОCH3
94
90
92
90
92
91
94
93
95
88
90
89
91
94
COC6H5
CH3
126–127
115–116
72–74
COCH2C6H5
COOC2H5
SO2CH3
CH3
d
e
CH3
CH3
105–106
178–180
109–191
143–144
oil
f
CONHC6H5
СОCH3
CH3
g
h
i
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH2C6H5
CH2C6H5
COC6H5
COCH2C6H5
COOC2H5
SO2CH3
j
oil
k
l
183–184
120–122
102–105
189–192
CONHC6H5
СОCH3
m
n
COC6H5
The same protocol can be readily used for the cyclization to 1,1-disubstituted 1,2,3,4-tetrahydro-
isoquinolines 7 (Table 5).
Table 5. Cyclisation to 1,1-disubstituted 1,2,3,4-tetrahydroisoquinolines.
7
a
b
c
d
e
n
o
p
r
s
R1
R2
CH3
R3
Yield [%]
mp, °C
123–125
143–146
oil
СОCH3
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
C2H5
C2H5
C6H5
C2H5
96
97
97
90
95
30
60
80
60
60
60
COC6H5
COCH2C6H5
COOC2H5
SO2CH3
COC6H5
СОCH3
CH3
CH3
CH3
55-56
CH3
123–125
164–166
76–81
CH2C6H5
CH3
COC6H5
SO2CH3
COC6H5
SO2CH3
CH3
90–92
CH3
100–102
103–133
138–141
CH3
t
C6H5
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 2011, 16
7025
Scheme 4. Formation of styrenes 8.
MeO
N
R1
MeO
MeO
NH R1
MeO
7
R2
PTSA
OH
R3
R3
5
R2
MeO
NH R1
R2
R3
MeO
8
Table 6. Formation of styrenes.
8
g
n
s
R1
R2
R3
CH3
C6H5
H
Yield [%]
mp, °C
72–75
48–50
COC6H5
COC6H5
COC6H5
SO2CH3
CH3
CH3
C6H5
C6H5
65
50
50
30
96–98
t
CH3
145–148
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 2011, 16
Figure 1. Change of spontaneous contractile activity of gastric smooth muscles preparation
7026
after using 1-substituted 1,2,3,4-tetrahydroisoquinoline derivatives and papaverine, normal
activity is taken for 100%.
120
100
80
60
100
110,3
99.5
107,5
40
20
0
3
Norm
1
2
3
papaverine
compounds
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%.
160
140
120
100
80
60
40
150
57
100
26
20
3
0
Norm
7e
7r
7t
papaverine
compounds
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).

Molecules 2011, 16
7027
The contractile activity against smooth muscle preparations of these compounds were not as high as
the activity of 7.
Figure 3. Change of spontaneous contractile activity of gastric smooth muscles preparation
after using styrenes and papaverine, normal activity is taken for 100%.
160
140
120
100
80
60
55
100
150
59
40
20
0
3
Norm
8n
8s
compounds
8t
papaverine
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.
13
1H-NMR and C-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

Molecules 2011, 16
7028
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 [53-56].
1
N-(2-Acetyl-4,5-dimethoxyphenethyl)benzamide (3b): H-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
13
(s, 1H), 7.34–7.47 (m, 4H), 7.77–7.80 (m, 1H); C-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
13
(s, 1H), 7.12 (s, 1H), 7.14–7.27 (m, 5H); C-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.
1
Ethyl 2-acetyl-4,5-dimethoxyphenethylcarbamate (3d): H-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.
1
N-(2-Acetyl-4,5-dimethoxyphenethyl)methanesulfonamide (3e): H-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
13
(t, J = 5.6, 1H, NH), 7.35 (s, 1H); C-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
1-(2-Acetyl-4,5-dimethoxyphenethyl)-3-phenylurea (3f): H-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.
1
N-(2-Benzoyl-4,5-dimethoxyphenethyl)acetamide (3g): H-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.

Molecules 2011, 16
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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].
1
N-(2-Benzoyl-4,5-dimethoxyphenethyl)methanesulfonamide (3k): H-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
1-(2-Benzoyl-4,5-dimethoxyphenethyl)-3-phenylurea (3l): H-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
13
(m, 1H), 7.74–7.77 (m, 2H); C-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.
1
N-(2-(1-Hydroxyethyl)-4,5-dimethoxyphenethyl)acetamide (4a): H-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.

Molecules 2011, 16
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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.
1
N-(2-(1-Hydroxyethyl)-4,5-dimethoxyphenethyl)-2-phenylacetamide (4c): H-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,
13
1H, NH), 6.52 (s, 1H), 6.99 (s, 1H), 7.11–7.15 (m, 2H), 7.24–7.31 (m, 3H); C-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.
Ethyl 2-(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.
1
N-(2-(1-Hydroxyethyl)-4,5-dimethoxyphenethyl)methanesulfonamide (4e): H-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),
13
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); C-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
1-(2-(1-Hydroxyethyl)-4,5-dimethoxyphenethyl)-3-phenylurea (4f): H-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
13
(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); C-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.
1
N-(2-(Hydroxy(phenyl)methyl)-4,5-dimethoxyphenethyl)acetamide (4g): H-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
13
(m, 5H); C-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.
1
N-(2-(Hydroxy(phenyl)methyl)-4,5-dimethoxyphenethyl)benzamide (4h): H-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),

Molecules 2011, 16
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13
7.70–7.67 (m, 2H); C-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.
1
Ethyl 2-(hydroxy(phenyl)methyl)-4,5-dimethoxyphenethylcarbamate (4j): H-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
13
(s, 1H), 6.87 (s, 1H), 7.21–7.37 (m, 5H); C-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.
1
N-(2-(Hydroxy(phenyl)methyl)-4,5-dimethoxyphenethyl)methanesulfonamide (4k): H-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,
13
1H), 5.93(t, J = 4.9, 1H, NH), 6.60 (s, 1H), 7.05 (s, 1H), 7.17–7.30 (m, 5H); C-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,

Molecules 2011, 16
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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.
1
N-(2-(2-Hydroxypropan-2-yl)-4,5-dimethoxyphenethyl)acetamide (5a): H-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),
13
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); C-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.
1
N-(2-(2-Hydroxypropan-2-yl)-4,5-dimethoxyphenethyl)-2-phenylacetamide (5c): H-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.
1
N-(2-(2-Hydroxy-1-phenylpropan-2-yl)-4,5-dimethoxyphenethyl)benzamide (5n): H-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.

Molecules 2011, 16
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1
N-(2-(2-Hydroxybutan-2-yl)-4,5-dimethoxyphenethyl)benzamide (5p): H-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),
13
7.70–7.79 (m, 2H); C-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.
1
N-(2-(1-Hydroxy-1-phenylethyl)-4,5-dimethoxyphenethyl)benzamide (5s): H-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
13
(d, J = 1.3,1H, NH) 6.77 (s, 1H), 7.15 (s, 1H), 7.24–7.48 (m, 10H); C-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.
1
N-(2-(1-Hydroxy-1-phenylpropyl)-4,5-dimethoxyphenethyl)methanesulfonamide (5t): H-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 [49-51].
1
(6,7-Dimethoxy-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)(phenyl)methanone (6b): H-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
1-(6,7-Dimethoxy-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-phenylethanone (6c): H-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
13
(m, 5H); C-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.

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Ethyl 6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (6d): known compound [52-55].
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 [58-60].
(6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)(phenyl)methanone (6h): known compound [58-60].
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 [61-63].
1
6,7-Dimethoxy-2-(methylsulfonyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (6k): H-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),
13
7.27–7.36 (m, 5H); C-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.
1
6,7-Dimethoxy-N,1-diphenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (6l): H-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-(1-Benzyl-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (6m): H-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),
13
7.17–7.27 (m, 5H); C-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,
13
1H), 6.77 (s, 1H); C-NMR: 170.3, 147.9, 147.1, 137.0, 126.3, 110.5, 109.6, 59.85, 56.1, 55.8, 44.1,

Molecules 2011, 16
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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.
1
Ethyl 6,7-dimethoxy-1,1-dimethyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (7d): H-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),
13
4.19 (q, J = 7.12, 7.09, 2H), 6.57 (s, 1H), 6.78 (s, 1H); C-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.
1
6,7-Dimethoxy-1,1-dimethyl-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (7e): H-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
(1-Benzyl-6,7-dimethoxy-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)(phenyl)methanone (7n): H-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-(1-Ethyl-6,7-dimethoxy-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (7o): H-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),
13
3.89 (s, 6H), 6.58 (s, 1H), 6.76 (s, 1H); C-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
(1-Ethyl-6,7-dimethoxy-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)(phenyl)methanone (7p): H-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

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(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.
1
(6,7-Dimethoxy-1-methyl-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)(phenyl)methanone (7s): H-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,
13
2H); C-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.
1
N-(2-(but-2-en-2-yl)-4,5-dimethoxyphenethyl)benzamide (8g): H-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.
1
N-(4,5-dimethoxy-2-(1-phenylprop-1-enyl)phenethyl)benzamide (8n): H-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);

Molecules 2011, 16
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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.

Molecules 2011, 16
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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.
© 2011 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).