Silica-supported polyphosphoric acid in the synthesis of 4-substituted tetrahydroisoquinoline derivatives

Article abstract of DOI:10.3390/molecules18021869

We report herein an application of an α-amidoalkylation reaction, as an alternative efficient synthesis of 4-aryl- and 4-methyl-1,2,3,4- tetrahydroisoquinoline derivatives. The amides required for this purpose would result from reaction of aminoacetaldehyde dimethylacetal with different substituted benzenes in polyphosphoric acid, followed by acylation of the obtained amines with different acid chlorides or sulfochlorides. We compared the cyclisation step using conventional (milieu of acetictrifluoracetic acid = 4:1) and solid supported reagents (SiO₂/PPA), as recovered, regenerated and reused without loss of its activity catalyst. We found that in comparison to conventional methods, the yields of the reaction are greater and the reaction time is shorter.

Full text of DOI:10.3390/molecules18021869

Molecules 2013, 18, 1869-1880; doi:10.3390/molecules18021869
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Silica-Supported Polyphosphoric Acid in the Synthesis of
4-Substituted Tetrahydroisoquinoline Derivatives
Stanimir Manolov, Stoyanka Nikolova and Iliyan Ivanov *
Department of Organic Chemistry, University of Plovdiv, 24 Tzar Assen str., 4000 Plovdiv, Bulgaria
* Author to whom correspondence should be addressed; E-Mail: iiiliyan@abv.bg or
ivanov@uni-plovdiv.bg; Tel.: +359-32-261-349; Fax: +359-32-261-403.
Received: 19 December 2012; in revised form: 21 January 2013 / Accepted: 22 January 2013 /
Published: 1 February 2013
Abstract: We report herein an application of an α-amidoalkylation reaction, as an
alternative efficient synthesis of 4-aryl- and 4-methyl-1,2,3,4-tetrahydroisoquinoline
derivatives. The amides required for this purpose would result from reaction of
aminoacetaldehyde dimethylacetal with different substituted benzenes in polyphosphoric
acid, followed by acylation of the obtained amines with different acid chlorides or
sulfochlorides. We compared the cyclisation step using conventional (milieu of acetic-
trifluoracetic acid = 4:1) and solid supported reagents (SiO2/PPA), as recovered,
regenerated and reused without loss of its activity catalyst. We found that in comparison to
conventional methods, the yields of the reaction are greater and the reaction time is shorter.
Keywords: 4-substituted tetrahydroisoquinoline; cherylline analogues; α-amidoalkylation
reaction; silica-supported polyphosphoric acid (SiO2-PPA)
1. Introduction
Very rare natural 4-aryl-1,2,3,4-tetrahydroisoquinoline alkaloids have been isolated from Crinum
powellii var. alba and other Crinum species [1]. Due to the uniqueness of the structure and potential
medicinal properties of the 4-arylisoquinoline derivatives [2–5], many synthetic routes for these
compounds [6–15] and especially cherylline have been reported. The Amaryllidaceae [6–16] have
been one of the most studied families of plants because of their alkaloids composition. In 1970,
Brossi et al. [1] isolated from Crinum powelli an alkaloid with a 4-aryl-1,2,3,4-tetrahydroisoquinoline
structure named cherylline. Some of them are valuable medicines with centrally stimulating,

Molecules 2013, 18
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thymoleptic, and antiarrhythmic actions [2,17]. Others are calcium antagonistic [18], and exhibit broad
spectrum of activity such as antibacterial [19], antiplasmodial [3,4,16,20,21], estrogen agonist/antagonist
activity [22], and serotin (5-HT) re-uptake [23].
The importance of these heterocyclic compounds has generated a considerable number of
synthetic approaches. Hence, the formation of the nitrogen-containing ring of 4-substituted 1,2,3,4-
tetrahydroisoquinolines has been achieved with several reactions such as Bischler-Napieralski [24–26],
intramolecular Horner [27], Friedel-Crafts [21,27–32] Pictet-Spengler [33], and oxazoline-driven
chemistry [34], among others [25,35–42]. Most of the reported methods for the synthesis of these
compounds are either multistep or low yielding.
In our previous investigations we report application of polyphosphoric acid (PPA) as a cyclisation
agent for the construction of tetrahydroisoquinoline ring systems. Polyphosphoric acid is a strong
mineral acid which has powerful dehydrating properties and is widely used for intramolecular and
intermolecular acylations, heterocyclic synthesis, and acid-catalyzed reactions. For instance, in recent
reports the cyclization reactions of N,N'-bis(oxotrifluoroalkenyl)-1,3-phenylenediamines in PPA
medium [43], the acylation of benzene and its derivatives with 2-, 3-, 4-aminobenzoic and
4-aminophenylacetic acid in PPA to aminobenzophenones [44], and the reaction of tryptamine with
carboxylic acid in PPA to afford 1-substitued-3,4-dihydro-9H--carboline derivatives [45], etc, were
described. However, the use of PPA has several drawbacks: since 10- to 50-fold excess is generally
employed, it is difficult to pour and stir at room temperature, and it is necessary to carefully neutralize
the reaction mixtures before the product extraction.
Recently, PPA/SiO2 has been used as an efficient heterogeneous catalyst for many organic
transformations. PPA/SiO2 has some advantages including its low cost, ease of preparation, and ease of
handling. In addition, the catalyst can be easily separated from the reaction mixtures by simple
filtration and is reusable. Previously [46], the conversion of carbonyl compounds into oxathioacetals or
dithioacetals using PPA/SiO2 and a convenient method for the synthesis of isoxazole derivatives using
PPA/SiO2 as a reusable catalyst have been reported [47]. In the last several years the development of
non-toxic, low cost, eco-friendly, recycable catalyst systems which give high productivity under mild
reaction conditions has received much attention in organic synthesis [48]. Solid supported catalysts [49,50]
have gained much prominence due to their inherent economic and environmental benefits, ease of
handling, easy catalyst separation and regeneration, thermal stability and long catalytic life [51]. Since
the activity and selectivity of a reagent dispersed on the surface of the support is improved as the
effective surface area of reagent can be increased manifold, they are expected to perform better than
the individual reagents [52]. Low toxicity, moisture, air tolerance and low price are other common
features that make the use of solid supported reagents attractive alternative to the conventional catalysts.
2. Results and Discussion
Our retrosynthetic analysis of 4-substituted 1,2,3,4-tetrahydroisoquinolines is depicted in Scheme 1.
We anticipated that 5 could be constructed from amides 4 via an α-amidoalkylation reaction. The
required amides 4 can be prepared from the amines 3 via acylation with different acid chlorides. The
amines 3 would arise from reaction [53] of aminoacetaldehyde dimethylacetal (1) with benzene or
substituted benzenes 2 (Scheme 2).

Molecules 2013, 18
Scheme 1. Retrosynthetic scheme for the synthesis of 4-substituted tetrahydroisoquinolines.
1871
R1
R1
R1
R1
R1
R1
R1
R1
R1
R1
R1
R1
NH2
NHR2
NR2
3
4
5
R1=H, OMe;
R2=COCH3, SO2CH3, COPhPh
Scheme 2. Synthesis of amines 3.
R1
R1
R1
O
R1
R1
R1
PPA
H2N
O
1
NH2
3
2
For the synthesis of the required starting materials Klumpp’s [53] protocol using amino acetals
and benzene in TfOH to give the corresponding products with good yields can be used. We carried out
the same reaction in polyphosphoric acid instead of TfOH. We found that aminoacetaldehyde
dimethylacetal reacts with excess of 1,2-dimethoxybenzene (veratrol) in PPA at rt for 5 to 10 min to
give a good (82%) yield of the corresponding product 3. The same product with unsubstituted benzene
was obtained after 30 min at 80 °C with 42% yield (Scheme 2, Table 1).
Table 1. Synthesis of amines 3.
3
a
b
R1
Yield, %
M.p., °C
47–49
oil
H
H
42
82
OCH3 OCH3
The amides 4 required for the next step of our synthesis, were prepared by acylation of the amines 3
with different acid chlorides or sulfochlorides. The next step was cyclization of the newly synthesized
amides (Scheme 3, Table 2).

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Scheme 3. Synthesis of 4-aryl tetrahydroisoquinolines.
R1
R1
R1
R1
R1
R1
R1
R1
R1
R1
CH2O, CH3COOH:CF3CCOOH = 4:1
NHR2
R2-Cl,
NH2
or CH2O, SiO2/PPA
NR2
NEt3, rt
R1
3
R1
4
5
Table 2. Synthesis of amides 4.
4
a
b
c
d
e
f
R
R1
H
H
R2
Yield, % M.p., °C
H
H
H
COCH3
SO2CH3
COPhPh
COCH3
80
98
94
91
90
97
85–86
138–139
192–193
126–128
49–52
H
OCH3 OCH3
OCH3 OCH3 SO2CH3
OCH3 OCH3 COPhPh
200–202
We compared the cyclisation step using either mixture of acetic-trifluoracetic acid = 4:1 or
silica-supported PPA (SiO2-PPA). We found that with SiO2-PPA the reaction yields are greater and the
reaction times are shorter (Table 3). The shortest time and best yield were achieved at 80 °C, using
0.06 g of catalyst and 1 h reflux. As described earlier [54] the catalyst was recovered quantitatively and
used in the reaction three times. The recovered catalyst did not show any significant loss of activity.
Table 3. Comparative yields of the compounds 5 synthesized through two conventional methods.
5
R
R1
R2
Yield, %
Yield, %
(CH3COOH:CF3COOH = 4:1)
(SiO2/PPA)
a
b
c
d
e
f
H
H
H
H
COCH3
SO2CH3
COPhPh
COCH3
SO2CH3
COPhPh
90
80
84
85
87
87
94
91
96
96
97
98
H
H
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
The same protocol was applied for the synthesis of 4-methyl-1,2,3,4-tetrahydroisoquinoline
derivatives which are interesting as potential anaesthetics and antispasmodics [55] (Scheme 4, Table 4).

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Scheme 4. Synthesis of 4-methyl tetrahydroisoquinolines.
c
NR2
NHR2
6
7
Reagents and Conditions: (c) CH2O, CH3COOH:CF3CCOOH = 4:1 rt or CH2O, SiO2/PPA.
Table 4. Synthesis of amides 6 and 4-methyl-1,2,3,4-tetrahydroisoquinolines 7.
6
a
b
c
R2
Yield, %
M.p., °C
Oil
COCH3
SO2CH3
COPhPh
R2
98
98
Oil
98
156–157
m.p., °C
Oil
7
a
b
c
Yield, %
89
COCH3
SO2CH3
COPhPh
93
66–67
Oil
96
3. Experimental
3.1. General
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
1
(BAS-IOCCP, Sofia). H-NMR and 13C-NMR spectra were taken in CDCl3 (unless otherwise
specified) at 250 MHz and 62.5 MHz respectively. Chemical shifts were given in part per million
(ppm) relative and were referenced to TMS ( = 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 vario EL III. TLC was carried out on precoated 0.2 mm Fluka silica gel 60
plates, using diethyl ether/n-hexane = 1:1 as chromatographic 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).
3.2. Preparation of PPA/SiO2 Catalyst General Procedure
PPA (4.0 g) was charged in the round-bottom flask, and CHCl3 (100 mL) was added. After the
mixture was stirred at 50 °C for 1 h, followed by SiO2 (16.0 g, 70–230 mesh) was added to the
solution, and the mixture was stirred for another 1 h. CHCl3 was removed by evaporation, and the
resulting solid was dried in vacuo at room temperature for 3 h. Used PPA/SiO2 was regenerated as
follows: PPA/SiO2 was recovered by filtration from the reaction mixture, and then it was put in the 50 mL
round-bottom flask and dried in vacuum at 100 °C for 2 h.

Molecules 2013, 18
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3.3. Typical Procedure for the Synthesis of 2-Amino-1,1-diphenylethanes 3
Aminoacetaldehyde dimethylacetal (1, 0,210 g, 2 mmol) was dissolved in the corresponding
benzene (22.47 mmol) in an open flask and polyphosphoric acid (3 g) was added. The reaction mixture
was stirred for 20 min at rt. After completion of the reaction, the mixture was poured over ice. The
organic layer was removed and after that the water layer the solution was neutralized with sodium
hydroxide, then extracted with CH2Cl2 (3 × 20 mL). Combined extracts were dried (Na2SO4) and
concentrated. The products, after evaporation of the solvent, were purified by column chromatography
on silica gel using Et2O as eluent.
3.4. 2,2-Diphenylethanamine (3a): Known Compound [53]
1
2,2-Bis(3,4-dimethoxyphenyl)ethanamine (3b). H-NMR: 1.97 (broad s, 2H, NH2), 3.29 (d, 2H,
J = 7.6 Hz), 3.85 (s, 6H), 3.87 (s, 6H), 3.93 (ddd, 1H, J = 4.0, 6.0, 10.0 Hz), 6.76–6.86 (m, 6H);
13C-NMR: 149.0, 147.7, 135.3, 119.7, 111.6, 111.3, 55.9, 53.8, 47.1; Anal. calc. for C18H23NO4: C,
68.12; H, 7.30; N, 4.41; found C, 68.18; H, 7.21; N, 4.38.
3.5. Acylation of Amines 3: Typical Procedure for the Synthesis of Amides 4 and 6
To solution of amine 3 (1 mmol) in dichloromethane (15 mL) equal amount of acetyl chloride,
methanesulfonyl chloride or biphenyl-4-carbonyl chloride was added. After 10 min a little excess of
triethylamine was added. After 30 min the solution was washed with diluted hydrochloric acid,
saturated solution of Na2CO3 and water. The organic layer was dried (Na2SO4), concentrated and
filtered on short column with neutral Al2O3.
1
N-(2,2-Diphenylethyl)acetamide (4a). H-NMR: 1.87 (s, 3H), 3.88 (dd, 2H, J = 5.9, 7.9 Hz), 4.17
(t, 1H, J = 8.0 Hz), 5.46 (s, 1H, NH), 7.22–7.25 (m, 6H), 7.28–7.31 (m, 4H); 13C-NMR: 170.1, 141.9,
128.8, 128.1, 126.9, 50.6, 43.9, 23.3; Anal. calc. for C16H17NO: C, 80.30; H, 7.16; N, 5.85; found C,
80.26; H, 7.23; N, 5.78.
N-(2,2-Diphenylethyl)methanesulfonamide (4b). 1H-NMR: 2.81 (s, 3H), 3.76 (d, 2H, J = 7.9 Hz), 4.20
(t, 1H, J = 8.0 Hz), 7.20–7.28 (m, 6H), 7.29–7.36 (m, 4H); 13C-NMR: 140.9, 129.0, 128.0, 127.3, 51.4,
47.6, 40.5; Anal. calc. for C15H17NO2S: C, 65.43; H, 6.22; N, 5.09; S, 11.64; found C, 65.37; H, 6.29;
N, 5.01; S, 11,71.
N-(2,2-Diphenylethyl)-[1,1'-biphenyl]-4-carboxamide (4c). 1H-NMR (CF3COOD): 4.36 (d, 2H,
J = 7.8 Hz), 4.48 (dd, 1H, J = 7.0, 9.4 Hz), 7.26–7.36 (m, 3H), 7.35 (s, 5H), 7.38–7.49 (m, 5H),
13
7.55–7.72 (m, 6H); C-NMR: 148.4, 139.9, 138.4, 128.7, 128.6, 128.5, 127.7, 127.5, 127.4, 127.2,
126.6, 121.0, 112.0, 107.5, 49.8, 46.5; Anal. calc. for C27H23NO: C 85.91; H, 6.14; N, 3.71; found C
85.97; H, 6.08; N, 3.78.
1
N-(2,2-Bis(3,4-dimethoxyphenyl)ethyl)acetamide (4d). H-NMR: 1.91 (s, 3H), 3.82–3.90 (m, 2H),
overlapped with 3.85 (s, 6H), 3.87 (s, 6H), 4.08 (t, 1H, J = 7.9 Hz), 5.46 (t, 1H, J = 5.7 Hz, NH), 6.76
(dd, 2H, J = 1.9, 5.8 Hz), 6.81 (d, 2H, J = 1.9 Hz), 6.83 (s, 1H), 6.86 (s, 1H); 13C-NMR: 170.0, 149.1,

Molecules 2013, 18
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147.9, 134.5, 119.7, 111.4, 111.3, 55.9, 55.8, 49.6, 44.0, 23.3; Anal. calc. for C20H25NO5: C, 66.83; H,
7.01; N, 3.90; found C, 66.75; H, 7.09; N, 3.86.
1
N-(2,2-Bis(3,4-dimethoxyphenyl)ethyl)methanesulfonamide (4e). H-NMR: 2.84 (s, 3H), 3.67 (d, 2H,
J = 7.7 Hz), 3.83 (s, 3H), 3.85 (s, 3H), 4.09 (t, 1H, J = 7.8 Hz), 4.32 (broad s, 1H, NH), 6.74 (dd, 2H,
13
J = 1.8, 9.8 Hz), 6.80 (d, 2H, J = 1.9 Hz), 6.83 (d, 2H, J = 8.2 Hz); C-NMR: 149.2, 148.2, 133.6,
119.6, 111.5, 111.4, 56.0, 55.9, 50.4, 47.7, 40.4; Anal. calc. for C19H25NO6S: C, 57.70; H, 6.37; N,
3.54; S, 8.11; found C, 57.78; H, 6.32; N, 3.61; S, 8.01.
1
N-(2,2-Bis(3,4-dimethoxyphenyl)ethyl)-[1,1'-biphenyl]-4-carboxamide (4f). H-NMR: 3.82 (s, 6H),
3.86 (s, 6H), 4.05 (dd, 2H, J = 5.7, 7.7 Hz), 4.24 (t, 1H, J = 7.9 Hz), 6.20 (t, 1H, J = 5.5 Hz, NH), 6.82
(dd,6H, J = 1.1, 10.9 Hz), 7.36–7.47 (m, 3H), 7.54–7.70 (m, 6H); 13C-NMR: 167.2, 149.2, 148.1,
144.3, 139.9, 134.6, 133.2, 128.9, 128.0, 127.3, 120.0, 111.6, 111.4, 55.9, 50.0, 44.6; Anal. calc. for
C31H31NO5: C, 74.83; H, 6.28; N, 2.81; found C, 74.75; H, 6.34; N, 2.79.
1
N-(2-Phenylpropyl)acetamide (6a). H-NMR: 1.20 (d, 3H, J = 7.0 Hz), 1.87 (s, 3H), 2.86 (ddd, 1H,
J = 2.2, 7.0, 13.2 Hz), 3.14 (ddd, 1H, J = 4.8, 8.8, 13.4 Hz), 3.56 (ddd, 1H, J = 6.1, 7.0, 13.1 Hz), 5.30
13
(broad s, 1H, NH), 7.14 (ddd, 3H, J = 1.8, 4.3, 5.5 Hz), 7.25 (dt, 2H, J = 2.0, 3.5 Hz); C-NMR:
170.0, 144.1, 128.8, 127.2, 126.8, 46.2, 39.7, 23.3, 19.5; Anal. calc. for C11H15NO: C, 74.54; H, 8.53;
N, 7.90; found C, 74.48; H, 8.60; N, 7.85.
1
N-(2-Phenylpropyl)methanesulfonamide (6b). H-NMR: 1.24 (d, 3H, J = 7.0 Hz), 2.69 (s, 3H), 2.89
(dd, 1H, J = 6.7, 14.7 Hz), 3.11–3.19 (m, 1H), 3.21–3.33 (m, 1H), 4.22 (t, 1H, J = 6.8 Hz, NH), 7.13–7.21
13
(m, 3H), 7.23–7.30 (m, 2H); C-NMR: 143.1, 128.9, 127.3, 127.2, 50.0, 40.4, 40.3, 19.0; Anal. calc.
for C10H15NO2S: C, 56.31; H, 7.09; N, 6.57; S, 15.03; found C, 56.26; H, 7.15; N, 6.49; S, 15.09.
1
N-(2,2-Bis(3,4-dimethoxyphenyl)ethyl)-[1,1'-biphenyl]-4-carboxamide (6c). H-NMR: 1.28 (d, 3H,
J = 7.0 Hz), 2.95–3.09 (m, 1H), 3.35 (ddd, 1H, J = 4.9, 8.7, 13.5 Hz), 3.78 (ddd, 1H, J = 6.1, 6.9, 13.2 Hz),
6.00 (t, 1H, J = 5.8 Hz, NH), 7.15–7.20 (m, 3H), 7.25–7.32 (m, 3H), 7.33–7.39 (m, 2H), 7.59–7.63 (m, 2H);
13C-NMR: 167.2, 144.2, 144.1, 140.0, 133.4, 128.93, 128.85, 128.0, 127.34, 127.29, 127.2, 127.0, 46.7,
39.9, 19.3; Anal. calc. for C31H31NO5: C, 74.83; H, 6.28; N, 2.81; found C, 74.79; H, 6.33; N, 2.78.
3.6. Cyclization of Amides 4 and 6 in Acetic/Trifluoracetic Acid Milieu: Typical Procedure
2-Phenylethylamides (3 mmol) and paraformaldehyde (5 mmol) were dissolved in a mixture of
CH3COOH/CF3COOH = 4:1 (5 mL) at 80–100 °C for 1 h. The solution was poured on the crushed ice
and extracted with CH2Cl2 (3 × 20 mL). The extract was washed with 20% aq.Na2CO3 (2 × 30 mL)
and dried (Na2SO4). The solvent was distilled and the products were purified by recrystallization (Et2O).
3.7. Cyclization of Amides 4 and 6 in SiO2-Supported Milieu: Typical Procedure
2-Phenylethylamides (3 mmol) and paraformaldehyde (5 mmol) were dissolved in a C2H4Cl2 (10 mL)
at 80 °C, 0.06 g of catalyst (SiO2/PPA) and 1h reflux. After the completion of the reaction the reaction
mixture was cooled and the catalyst was separated by simple filtration.

Molecules 2013, 18
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1
1-(4-Phenyl-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (5a). H-NMR: 1.67 (s, 3H), 3.82 (d, 2H,
J = 4.4 Hz), 4.23 (t, 1H, J = 4.2 Hz), 4.52 (d, 1H, J = 17.1 Hz), 5.23 (d, 1H, J = 17.4 Hz), 6.96–7.06
13
(m, 3H), 7.22–7.29 (m, 6H); C-NMR: 169.9, 142.7, 136.0, 133.6, 129.5, 128.7, 128.5, 127.1, 126.6,
51.2, 45.4, 44.3, 20.8; Anal. calc. for C17H17NO: C, 81.24; H, 6.82; N, 5.57; O, 6.37; found C, 81.28;
H, 6.77; N, 5.60.
2-(Methylsulfonyl)-4-phenyl-1,2,3,4-tetrahydroisoquinoline (5b). 1H-NMR: 3.47 (dd, 1H, J = 7.4, 12.5 Hz),
3.86 (ddd, 1H, J = 1.0, 5.0, 12.4 Hz), 4.33 (t, 1H, J = 6.3 Hz), 4.57 (q, 2H, J = 15.4, 15.38 Hz),
6.94–6.98 (m, 1H), 7.11–7.18 (m, 4H), 7.21–7.31 (m, 4H); 13C-NMR: 142.5, 136.2, 132.2, 129.9,
128.9, 128.7, 127.2, 127.0, 126.3, 50.9, 47.6, 45.1, 36.4; Anal. calc. for C16H17NO2S: C, 66.87; H,
5.96; N, 4.87; S, 11.16; found C, 66.91; H, 5.91; N, 4.90; S, 11.11.
1
Biphenyl-4-yl(4-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (5c). H-NMR (CF3COOD): 4.36
(d, 2H, J = 7.8 Hz), 4.48 (dd, 1H, J = 7.0, 9.4 Hz), 7.26–7.36 (m, 3H), 7.35 (s, 5H), 7.38–7.49 (m, 5H),
13
7.55–7.72 (m, 6H); C-NMR: 148.4, 139.9, 138.4, 128.7, 128.6, 128.5, 127.7, 127.5, 127.4, 127.2,
126.6, 121.0, 112.0, 107.5, 49.8, 46.5; Anal. calc. for C28H23NO C, 86.34; H, 5.95; N, 3.60; found C,
86.39; H, 5.89; N, 3.58.
1
1-(4-(3,4-Dimethoxyphenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (5d). H-NMR
(CDCl3): 1.66 (s, 3H), 3.74 (s, 3H), 3.81 (s, 3H), 3.87 (s, 3H), 3.90 (s, 3H), 4.90 (t, 1H, J = 0.96 Hz),
4.93 (d, 2H, J = 1.09 Hz), 5.34–5.35 (m, 2H), 6.47 (s, 1H), 6.53 (s, 1H), 6.68–6.69 (m, 2H), 6.82 (s,
13
1H); C-NMR (CDCl3): 169.9, 149.0, 148.3, 148.1, 148.0, 147.9, 135.5, 120.7, 111.8, 111.4, 111.2,
109.2, 108.6, 56.2, 56.0, 55.93, 55.89, 51.5, 44.6, 43.9, 20.9. Anal. calc. for C21H25NO5: C, 67.91; H,
6.78; N, 3.77; found C, 67.96; H, 6.74; N, 3.82.
1
4-(3,4-Dimethoxyphenyl)-6,7-dimethoxy-2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline (5e). H-NMR
(CDCl3): 2.72 (s, 3H), 3.41 (dd, 1H, J = 7.42, 12.37 Hz), 3.72 (s, 3H), 3.81–3.86 (m, 1H), overlapped
with 3.84 (s, 3H), 3.89 (s, 3H), 3.90 (s, 3H), 4.21 (dd, 1H, J = 5.58, 6.24 Hz), 4.51 (q, 2H, J = 6.25,
15.0 Hz), 6.46 (s, 1H), 6.64 (s, 1H), 6.67–6.71 (m, 2H), 6.81–6.85 (m, 1H); 13C-NMR (CDCl3): 149.0,
148.2, 148.1, 135.0, 128.2, 124.1, 121.0, 112.1, 111.9, 111.2, 108.5, 56.0, 55.9, 51.1, 47.3, 44.3, 36.3.
Anal. calc. for C20H25NO6S: C, 58.95; H, 6.18; N, 3.44; S, 7.87; found C, 58.99; H, 6.14; N, 3.45; S, 7.81.
Biphenyl-4-yl[4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl]methanone (5f).
1H-NMR: 3.73 (s, 3H), 3.76 (s, 3H), 3.91 (s, 3H), 3.94 (s, 3H), 4.09 (s, 1H), 4.65 (d, 1H, J = 17.0 Hz),
5.34 (d, 1H, J = 16.6 Hz), 6.51 (s, 2H), 6.81 (d, 2H, J = 7.7 Hz), 6.92 (d, 2H, J = 6.8 Hz), 7.36–7.50
(m, 6H), 7.57–7.65 (m, 4H); 13C-NMR: 171.3, 149.2, 148.5, 148.14, 148.07, 142.2, 140.2, 135.2,
134.5, 128.9, 127.5, 127.4, 127.1, 126.8, 125.3, 112.0, 111.7, 111.2, 108.8, 56.03, 55.99, 55.94, 55.87,
52.2, 51.8, 44.6. Anal. calc. for C32H31NO5: C, 75.42; H, 6.13; N, 2.75; found C, 75.50; H, 6.10; N, 2.81.
4. Conclusions
In conclusion, we have developed a highly efficient SiO2-PPA catalyzed method for the
construction of 4-aryl- or 4-methyl-1,2,3,4-tetrahydroisoquinoline ring systems, as analogues of
biologically-active compounds. The catalyst is completely recoverable and the efficiency of the

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1877
catalyst remains unaltered even after three to four cycles. It is also noticed that the cyclisation using
PPA–SiO2 proceeds rapidly and is superior to the reported procedures with respect to yield and amount
of the catalyst employed.
Acknowledgments
We acknowledge financial support from the National Fund for scientific research DO-02-131 and
DO-02-195.
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Sample Availability: Samples of the compounds are available from the authors.
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