Synthesis of 4-(trifluoromethyl)isoquinolines. Influence of trifluoromethyl group on the Pictet-Gams ring closure reaction

Article abstract of DOI:10.1016/S0040-4020(01)00836-5

Treatment of N-acyl-2-methoxy-2-(trifluoromethyl)arylethylamines under Pictet-Gams conditions afforded 4-methoxy-4-trifluoromethyl-3,4-dihydroisoquinolines which were aromatised by base catalysed methanol elimination. Earlier we described the synthesis of 2-oxazolines by conducting the Pictet-Gams sequence with N-acyl-2-hydroxy-2-(trifluoromethyl)arylethylamines. The operation of these two pathways is explained by the influence of the trifluoromethyl group.

Full text of DOI:10.1016/S0040-4020(01)00836-5

TETRAHEDRON
Pergamon
Tetrahedron 57 )2001) 8573±8580
Synthesis of 4-ꢀtri¯uoromethyl)isoquinolines. In¯uence of
tri¯uoromethyl group on the Pictet±Gams ring closure reaction
p
   Â
Laszlo Poszavacz and Gyula Simig
Chemical Research Division, EGIS Pharmaceuticals Ltd., P.O. Box 100, H-1475 Budapest, Hungary
Received 24 May 2001; revised 17 July 2001; accepted 8 August 2001
AbstractÐTreatment of N-acyl-2-methoxy-2-)tri¯uoromethyl)arylethylamines under Pictet±Gams conditions afforded 4-methoxy-4-
tri¯uoromethyl-3,4-dihydroisoquinolines which were aromatised by base catalysed methanol elimination. Earlier we described the synthesis
of 2-oxazolines by conducting the Pictet±Gams sequence with N-acyl-2-hydroxy-2-)tri¯uoromethyl)arylethylamines. The operation of these
two pathways is explained by the in¯uence of the tri¯uoromethyl group. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Derivatives of 1-styrylisoquinolines, in particular, 1-)4-
¯uorostyryl)-6,7-)methylenedioxy)isoquinoline )1) display
remarkable anxiolytic activity without sedative side-
effects.1 Within the framework of our systematic struc-
ture±activity relationship studies we became interested in
the synthesis of related 4-)tri¯uoromethyl)isoquinoline
derivatives )Scheme 1).
2
In a recentpublicaiton
N-acyl-2-hydroxy-2-)tri¯uoromethyl)arylethylamines
we disclosed that cyclisation of
2
under Pictet±Gams conditions )heating with phosphorus
oxychloride in toluene for 4 h at 958C) afforded 2-oxazo-
lines 3 instead of the expected isoquinolines 4 )Scheme 2).
The intermediacy of 2-oxazolines in Pictet±Gams cyclisa-
tion of N-acyl-2-hydroxyarylethylamines to isoquinolines
has been demonstrated.3,4 However, tri¯uoromethyl substi-
Scheme 2. R: CH3, styryl; R1: alkoxy; R2: H, alkoxy.
tuted 2-oxazolines 3 could not be converted to isoquinolines
even under vigorous conditions )phosphorus pentoxide,
boiling decaline).
Nevertheless, we have accomplished the synthesis of
1-styryl-4-)tri¯uoromethyl)isoquinolines under Pictet±
Gams conditions starting from N-acyl-2-methoxy-2-
)tri¯uoromethyl)arylethylamines, which we report here.
2. Result and discussion
Scheme 1.
N-Acyl-2-methoxy-2-)tri¯uoromethyl)arylethylamines
8
Keywords: 4-)tri¯uoromethyl)isoquinoline; Pictet±Gams cyclisation;
methanol elimination; destabilising effect of the tri¯uoromethyl group.
Corresponding author. Tel.: 136-1-2655543; fax: 136-1-2655613;
e-mail: simig@freemail.hu
and 9 were prepared as shown in Scheme 3. Compounds 6
were prepared conveniently from tri¯uoroacetophenones 52
similarly to their unsubstituted analogue `Mosher's nitrile'.5
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020)01)00836-5

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L. Poszavacz, G. Simig / Tetrahedron 57 /2001) 8573±8580
8574
Scheme 3.
Amides 8 and 9 were obtained by reduction of nitriles 6 with
sodium borohydride in the presence of cobalt chloride to
amines 7 and subsequent acylation with the corresponding
acid chlorides or acetic anhydride.
as a model compound to look for reaction conditions result-
ing in methanol elimination )Scheme 4). Reaction of 11a
with hydrogen bromide in glacial acetic acid afforded
dihydroxy-3,4-dihydroisoquinoline 14 by hydrolysis of
both methoxy groups. Treatment of 11a with concentrated
sulphuric acid under more vigorous acidic conditions gave
aromatic isoquinoline 15. However, aromatisation was
accompanied with the undesirable hydrolysis of the
6-methoxy substituent.
Treatment of N-acyl-2-methoxy-2-)tri¯uoromethyl)aryl-
ethylamines 8 and 9 under Pictet±Gams conditions )heating
with phosphorus oxychloride in toluene or without solvent
for 16 h at90 8C) afforded isoquinolines in good yields.
Interestingly enough, the products were not type 4 aromatic
derivatives as usual in Pictet±Gams cyclisations, but 10 and
11 4-methoxy-4-tri¯uoromethyl-3,4-dihydroisoquinolines.
After all, our target compounds 12 and 13 as well were
obtained by base )potassium hydroxide) catalysed methanol
elimination from 3,4-dihydroisoquinolines 10 and 11, under
conditions unusual for similar reactions in isoquinoline
chemistry.
The non-occurrence of methanol elimination under Pictet±
Gams conditions can be attributed to the presence of the
tri¯uoromethyl group destabilising the cationic transition
state of the acid catalysed elimination. 4,6-Dimethoxy-4-
tri¯uoromethyl-3,4-dihydroisoquinoline )11a) was selected
Condensation of 1-methylisoquinoline 12a with benzalde-
hyde in acetic anhydride afforded 13a in 60% yield.6,7

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L. Poszavacz, G. Simig / Tetrahedron 57 /2001) 8573±8580
8575
Scheme 4.
Interestingly, the reaction of 11a with benzaldehyde under
similar conditions also gave aromatic isoquinoline 13a, i.e.
the condensation reaction was accompanied by methanol
elimination )Scheme 3).
Dimethyl sulfate )38.0 ml, 50.45 g, 0.40 mol) was added
and the mixture was stirred for 5 h at 608C. After standing
overnight the solid was ®ltered off. The ®ltrate was evapo-
rated. The resulting oil was puri®ed by distillation under
reduced pressure )bp 80±828C, 7 mmHg) to afford nitrile
6a )60.0 g, 65%) as a colourless oil; IR )KBr) 2850, 2250,
The observed dissimilar reactivities can be explained by
the different capability of N-acyl-2-hydroxy-2-)tri¯uoro-
methyl)arylethylamines )2) and their 2-methoxy counter-
parts )8 and 9) to form 2-oxazolines under Pictet±Gams
conditions. Transformation of 2-oxazolines to isoquinolines
formed in the cyclisation reaction of 2-hydroxy derivatives
is hindered because of the destabilising effect of the
tri¯uoromethyl group on the expected cationic intermediate
of the reaction.8 The formation of the isoquinolines in the
case of 2-methoxy derivatives demonstrates that 2-oxazo-
lines do not form in the course of this reaction at all.
1190 cm21 1H NMR )250 MHz, CDCl3): 7.41 )1H, t,
;
Jˆ8.0 Hz); 7.30±7.00 )3H, m); 3.83 )3H, s); 3.49 )3H, s).
Anal. Calcd for C11H10F3NO2 )245.20): C, 53.88; H, 4.11;
N, 5.71. Found: C, 53.50; H, 4.10; N, 5.51.
3.1.2. Preparation of 3,3,3-tri¯uoro-2-methoxy-2-ꢀ3,4-
methylenedioxyphenyl)propionitrile ꢀ6b). A mixture of
a,a,a-tri¯uoro-3,4-methylenedioxyacetophenone
)5b,
32.72 g, 0.15 mol)2 and sodium cyanide )14.70 g,
0.30 mol) was stirred for 15 min at ambient temperature in
1,2-dimethoxyethane. Anhydrous potassium carbonate
)20.73 g, 0.15 mol) and dimethyl sulfate )42.7 ml, 56.76 g,
0.45 mol) was added and the mixture was stirred for 3 h at
ambient temperature. After addition of aqueous ammonium
hydroxide solution )25%, 42 ml) and water )330 ml) the
mixture was extracted with ethyl acetate )2£160 ml). The
organic layer was separated, washed with brine )2£160 ml),
dried )MgSO4) and evaporated. The residue was puri®ed by
distillation under reduced pressure )bp 78±888C,
0.3 mmHg) to give nitrile 6b )27.60 g, 71%) as a colourless
oil; IR )KBr) 2909; 2248; 1492; 1254; 1189 cm21; 1H NMR
)200 MHz, CDCl3): 7.17 )1H, dd, Jˆ8.1, 1.8 Hz); 7.05 )1H,
d, Jˆ1.8 Hz); 6.89 )1H, d, Jˆ8.1 Hz); 6.05 )2H, s); 3.48
)3H, s). Anal. Calcd for C11H8F3NO3 )259.19): C, 50.98; H,
3.11; N5.40. Found: C, 50.75; H, 3.17; N, 5.45.
3. Experimental
3.1. General
The melting points were determined on a BuÈchi 535
aparatus and were uncorrected. The IR spectra were
recorded on an Aspect2000 compuetr conrtolled Bruker
IFS-113n vacuum optic FT spectromer using KBr pellets
1
or ®lms of liquids. The H NMR and 13C NMR spectra
were recorded on a Bruker WM 250 FT, or a Varian
Gemini-200, or a Varian Unity Inova 400 spectrometer, in
deuteriochloroform and dimethylsulfoxide-d6 as solvents.
Chemical shifts were reported as d values )ppm) down
®eld from internal tetramethylsilane. The EI MS were
recorded on a Kratos MS25FRA mass spectrometer at
70 eV.
3.2. General procedure for the synthesis of amines 7
To a mixture of nitrile 6 )0.10 mol) and cobaltchloride
hexahydrate )23.78 g, 0.10 mol) in methanol )250 ml) was
added sodium borohydride )3.78 g, 0.10 mol) at0 8C. After
standing overnight at room temperature the solvent was
evaporated. Water )500 ml) and aqueous hydrochloric acid
solution )2N) was added and the mixture was stirred for 1 h.
3.1.1. Preparation of 3,3,3-tri¯uoro-2-methoxy-2-ꢀ3-
methoxyphenyl)propionitrile ꢀ6a). A mixture of a,a,a-
tri¯uoro-3-methoxyacetophenone )5a, 61.25 g, 0.30 mol)2
and potassium cyanide )32.56 g, 0.50 mol) was stirred for
30 min at ambient temperature in 1,2-dimethoxyethane.

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L. Poszavacz, G. Simig / Tetrahedron 57 /2001) 8573±8580
8576
The pH was adjusted to 13 by adding aqueous sodium
hydroxide )20%) solution and the mixture was extracted
with dichloromethane )3£300 ml). After drying )MgSO4)
and evaporation the residual oil was distilled in vacuo.
4.06 )1H, ddd, Jˆ14.9, 5.4, 1.3 Hz); 3.83 )3H, s); 3.39 )3H,
s); 13C NMR )62,9 MHz, CDCl3): 163.5 )d, 1JCFˆ249.2 Hz);
3
159.7; 140.4; 134.8; 130.7; 119.6 )d, JCFˆ8.8 Hz); 129.3
1
)q, JCFˆ289.1 Hz); 122.4; 119.6; 119.4; 117.8; 115.8 )d,
2JCFˆ22.6 Hz); 114.3; 113.5; 80.5 )q, 2JCFˆ27.2 Hz); 55.2;
52.5; 40.9. Anal. Calcd for C20H19F4NO3 )397.37): C, 60.45;
H, 4.82; N, 3.52. Found: C, 60.31; H, 4.80; N, 3.55.
3.2.1. 3,3,3-Tri¯uoro-2-methoxy-2-ꢀ3-methoxyphenyl)-
propylamine ꢀ7a). This compound was obtained as a
colourless oil )15.20 g, 61%), bp 103±1048C )4 mmHg);
1
IR )KBr) 2800; 1174; 1119 cm21; H NMR )250 MHz,
3.3.3. N-[2-Methoxy-2-ꢀ3-methoxyphenyl)-2-ꢀtri¯uoro-
methyl)ethyl]-4-ꢀtri¯uoromethyl)cinnamic amide ꢀ8c).
This compound was obtained as colourless crystals
)16.10 g; 72%), mp 85±868C; IR )KBr) 3436; 1672; 1324;
CDCl3): 7.33 )1H, t, Jˆ8.2 Hz); 7.05 )2H, m); 6.90 )1H,
ddd, Jˆ8.2, 2.5, 0.8 Hz); 3.82 )3H, s); 3.42 )3H, s); 3.36
)1H, d, Jˆ14.6 Hz); 3.13 )1H, d, Jˆ14.6 Hz); 1.20 )2H, bs);
13C NMR )62.9 MHz, CDCl3): 159.7; 135.8; 129.4; 125.4
1133 cm21 1H NMR )400 MHz, CDCl3): 7.64 )1H, d,
;
1
2
)q, JCFˆ289.6 Hz); 119.2; 113.5; 82.2 )q, JCFˆ24.8 Hz);
54.9; 52.5; 45.7. Anal. Calcd for C11H14F3NO2 )249.23): C,
53.01; H, 5.66; N, 5.62. Found: C, 52.70; H, 5.53; N, 5.78.
Jˆ15.6 Hz); 7.64±7.60 )4H, m); 7.35 )1H, t, Jˆ8.2 Hz);
7.10±7.06 )2H, m); 6.97±6.92 )1H, m); 6.46 )1H, d,
Jˆ15.6 Hz); 5.92 )1H, bs); 4.27 )1H, dd, Jˆ14.9, 5.4 Hz);
4.05 )1H, ddq, Jˆ14.9, 5.4, 1.1 Hz); 3.83 )3H, s); 3.40 )3H,
s); 13C NMR )100.6 MHz, CDCl3): 165.0; 159.9; 140.1;
3.2.2. 3,3,3-Tri¯uoro-2-methoxy-2-ꢀ3,4-methylenedioxy-
phenyl)propylamine ꢀ7b). This compound was obtained
2
138.1; 134.9; 131.4 )q, JCFˆ32.8 Hz); 129.8; 128.0;
1
3
as
a colourless oil )17.9 g, 68%), bp 114±1168C
126.5 )q, JCFˆ278.9 Hz); 125.8 )q, JCFˆ3.8 Hz); 124.8
)1.1 mmHg); IR )KBr) 2951; 1492; 1167 cm21; H NMR
)200 MHz, CDCl3): 6.97 )1H, m); 6.93 )1H, ddd, Jˆ8.2, 1.8,
0.4 Hz); 6.83 )1H, dd, Jˆ8.2, 0.4 Hz); 5.97 )2H, s); 3.39
)3H, q, Jˆ1.2 Hz); 3.36 )1H, d, Jˆ14.6 Hz); 3.12 )1H, dq,
Jˆ14.6, 1.6 Hz); 1.28 )2H, bs); 13C NMR )100.6 MHz,
1
1
)q, JCFˆ288.0 Hz); 122.5; 119.5; 114.5; 113.6; 80.7 )q,
2JCFˆ26.7 Hz); 55.4; 52.7; 41.2. Anal. Calcd for
C21H19F6NO3 )447.38): C, 56.38; H, 4.28; N, 3.13. Found:
C, 56.45; H, 4.32; N, 3.18.
1
CDCl3): 147.9; 147.7; 127.8; 125.3 )q, JCFˆ289.5 Hz);
3.3.4. N-[2-Methoxy-2-ꢀ3-methoxyphenyl)-2-ꢀtri¯uoro-
120.8 )q, Jˆ1.5 Hz); 108.0; 107.7 )q, Jˆ1.5 Hz); 101.2;
methyl)ethyl]-4-nitrocinnamic
compound was obtained as colourless crystals )13.50 g;
amide
ꢀ8d).
This
2
82.0 )q, JCFˆ24.8 Hz); 52.3 )q, Jˆ289.6 Hz); 45.3 )q,
3JCFˆ1.1 Hz). Anal. Calcd for C11H12F3NO3 )263.22): C,
64%), mp 80±818C; IR )KBr) 1659; 1515; 1345; 1168;
50.19; H, 4.60; N, 5.32. Found: C, 49.96; H, 4.58; N, 5.34.
1120 cm21 1H NMR )200 MHz, CDCl3): 8.23 )2H, d,
;
Jˆ8.8 Hz); 7.67 )1H, d, Jˆ15.6 Hz); 7.65 )2H, d,
Jˆ8.8 Hz); 7.37 )1H, t, Jˆ8.2 Hz); 7.15±7.03 )2H, m);
7.00±6.90 )1H, m); 6.55 )1H, d, Jˆ15.6 Hz); 6.02 )1H, t,
Jˆ5.2 Hz); 4.30 )1H, dd, Jˆ15.0, 5.5 Hz); 4.04 )1H, ddq,
Jˆ15.0, 5.5, 1.6 Hz); 3.84 )3H, s); 3.40 )3H, s); 13C NMR
)50.3 MHz, CDCl3): 164.7; 159.9; 148.3; 140.9; 139.2;
3.3. General procedure for synthesis of amides 8
To a stirred mixture of amine 7 )50 mmol) in ether )20 ml)
and sodium carbonate )5.3 g, 50 mmol) in water )50 ml) was
added a solution of cinnamoyl chloride )50 mmol) in ether
)50 ml) at0 8C. After stirring 2 h at room temperature, the
resulting crystalline product was ®ltered and recrystallised
from a mixture of 2-propanol and water.
1
134.8; 129.9; 128.5; 124.9 )q, JCF2ˆ288.8 Hz); 124.3;
124.2; 119.5; 114.5; 113.6; 80.7 )q, JCFˆ26.3 Hz); 55.3;
52.7; 41.3. Anal. Calcd for C20H19F3N2O5 )424.38): C,
56.61; H, 4.51; N, 6.60. Found: C, 56.36; H, 4.52; N, 6.60.
3.3.1. N-[2-Methoxy-2-ꢀ3-methoxyphenyl)-2-ꢀtri¯uoro-
methyl)ethyl]cinnamic amide ꢀ8a). This compound was
obtained as colourless crystals )11.48 g; 61%), mp 72±
3.3.5. N-[2-Methoxy-2-ꢀ3,4-methylenedioxyphenyl)-2-ꢀtri-
¯uoromethyl)ethyl]-4-ꢀtri¯uoromethyl)cinnamic amide
ꢀ8e). This compound was obtained as colourless crystals
)19.61 g; 85%), mp 104±1068C; IR )KBr) 3310; 1665;
738C; IR )KBr) 1662; 1630; 1179 cm21
;
1H NMR
)250 MHz, CDCl3): 7.63 )1H, d, Jˆ15.6 Hz); 7.55±7.45
)2H, m); 7.40±7.30 )4H, m); 7.10±7.05 )2H, m); 6.99±
6.90 )1H, m); 6.39 )1H, d, Jˆ15.6 Hz); 5.89 )1H, bs);
4.27 )1H, dd, Jˆ15.0, 5.4 Hz); 4.08 )1H, dd, Jˆ15.0,
5.4 Hz); 3.83 )3H, s); 3.39 )3H, q, Jˆ0.8 Hz); 13C NMR
)50,3 MHz, CDCl3): 165.7; 159.8; 141.7; 135.0; 134.6;
1630; 1326; 1170; 1125 cm21
;
1H NMR )200 MHz,
CDCl3): 7.66 )1H, d, Jˆ15.4 Hz); 7.61 )4H, m); 7.05±
6.95 )2H, m); 6.85 )1H, d, Jˆ7.7 Hz); 6.48 )1H, d,
Jˆ15.4 Hz); 6.01 )2H, s); 5.96 )1H, bs); 4.24 )1H, dd,
Jˆ14.9, 5.1 Hz); 4.04 )1H, dd, Jˆ14.9, 5.1 Hz); 3.36 )3H,
s); 13C NMR )100.6 MHz, CDCl3): 165.1; 148.4; 148.2;
1
129.8; 129.7; 128.8; 127.8; 124.9 )q, JCFˆ288.4 Hz);
4
2
2
140.1; 138.0 )q, JCFˆ1.5 Hz); 131.3 )q, JCFˆ32.4 Hz);
120.1; 119.5; 114.5; 113.6; 80.6 )q, JCFˆ26.3 Hz); 55.3;
3
128.0; 126.8; 125.7 )q, JCFˆ3.8 Hz); 124.8 )q,
52.6; 40.9. Anal. Calcd for C20H20F3NO3 )379.38): C, 63.32;
H, 5.31; N, 3.69. Found: C, 63.12; H, 5.27; N, 3.76.
1
1
JCFˆ288.0 Hz); 123.8 )q, JCFˆ274.3 Hz); 122.5; 121.2;
2
108.3; 107.9; 101.5; 80.4 )q, JCFˆ26.7 Hz); 52.4; 41.0.
Anal. Calcd for C21H17F6NO4 )461.36): C, 54.67; H, 3.71;
N, 3.04. Found: C, 54.46; H, 3.70; N, 3.05.
3.3.2. N-[2-Methoxy-2-ꢀ3-methoxyphenyl)-2-ꢀtri¯uoro-
methyl)ethyl]-4-¯uorocinnamic amide ꢀ8b). This
compound was obtained as colourless crystals )14.81 g;
75%), mp 100±1018C; IR )KBr) 3293; 1661; 1628; 1227;
3.4. General procedure for synthesis of acetamides 9
1149 cm21 1H NMR )200 MHz, CDCl3): 7.59 )1H, d,
;
Jˆ15.6 Hz); 7.51±7.44 )2H, m); 7.40±7.30 )1H, m);
7.10±7.00 )4H, m); 7.00±6.91 )1H, m); 6.31 )1H, d,
Jˆ15.6 Hz); 5.88 )1H, bs); 4.27 )1H, dd, Jˆ14.9, 5.4 Hz);
To a solution of amine 7 )50 mmol) in ethyl acetate )90 ml)
was added acetic anhydride )4.9 ml, 5.31 g, 52 mmol) at
08C. After stirring for 2 h at room temperature, water

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L. Poszavacz, G. Simig / Tetrahedron 57 /2001) 8573±8580
8577
1
)90 ml) was added and the layers were separated. The
aqueous layer was extracted with ethyl acetate )2£60 ml).
The combined organic layers were dried )MgSO4) and
evaporated. The residue was recrystallised from a mixture
of 2-propanol and water.
132.3; 129.8; 129.3; 124.4 )q, JCFˆ287.5 Hz); 119.0;
2
115.9; 115.8; 114.7; 75.0 )q, JCFˆ28.5 Hz); 55.8; 53.3;
42.2. Anal. Calcd for C20H19ClF3NO2 )397.82): C, 60.38;
H, 4.81; Cl, 8.91; N, 3.54. Found: C, 60.24; H, 4.84; Cl,
8.92; N, 3.49.
3.4.1. N-[2-Methoxy-2-ꢀ3-methoxyphenyl)-2-ꢀtri¯uoro-
methyl)ethyl]acetamide ꢀ9a). This compound was
obtained as colourless crystals )14.50 g; 98%), mp 74±
3.5.2.
1-ꢀ4-Fluorostyryl)-4,6-dimethoxy-4-tri¯uoro-
methyl-3,4-dihydroisoquinoline ꢀ10b). This compound
was obtained as colourless crystals )67%), mp 92±938C;
758C; IR )KBr) 3330; 1613; 1119 cm21
;
1H NMR
IR )KBr) 2959; 1646; 1510; 118 cm21
;
1H NMR
)200 MHz, CDCl3): 7.34 )1H, t, Jˆ8.3 Hz); 7.03 )2H, m);
6.93 )1H, s); 5.79 )1H, s); 4.13 )1H, dd, Jˆ14.8, 5.4 Hz);
3.90 )1H, ddd, Jˆ14.8, 5.4, 1.4 Hz); 3.83 )3H, s); 3.35 )3H,
q, Jˆ0.9 Hz); 1.99 )3H, s); 13C NMR )50.3 MHz, CDCl3):
)400 MHz, CDCl3): 7.70 )1H, d, Jˆ8.6 Hz); 7.53 )2H, m);
7.42 )1H, d, Jˆ15.9 Hz); 7.24 )1H, d, Jˆ2.6 Hz); 7.14 )1H,
d, Jˆ15.9 Hz); 7.10±7.02 )3H, m); 4.26 )1H, d,
Jˆ17.2 Hz); 4.17 )1H, d, Jˆ17.2 Hz); 3.90 )3H, s); 3.32
)3H, s); 13C NMR )100.6 MHz, CDCl3): 163.1 )d,
1JCFˆ249.1 Hz); 161.8; 161.6; 135.5; 132.6; 132.4; 129.0
1
170.1; 159.9; 135.0; 129.8; 124.9 )q, JCFˆ288.8 Hz);
2
119.6; 114.5; 113.9; 80.7 )q, JCFˆ26.3 Hz); 55.4; 52.7;
3
1
41.0; 23.2. Anal. Calcd for C13H16F3NO3 )291.27): C,
53.61; H, 5.54; N, 4.81. Found: C, 53.48; H, 5.50; N, 4.75.
)d, JCFˆ8.4 Hz); 128.1; 125.2 )q, JCFˆ286.1 Hz); 123.6
4
2
)d, JCFˆ2.3 Hz); 123.0; 115.8 )d, JCFˆ22.1 Hz); 114.8;
2
112.8; 75.1 )q, JCFˆ27.5 Hz); 55.6; 52.6; 49.4. Anal.
3.4.2.
N-[2-Methoxy-2-ꢀ3,4-methylenedioxyphenyl)-2-
Calcd for C20H17F4NO2 )379.35): C, 63.32; H, 4.52; N,
3.69. Found: C, 63.05; H, 4.48; N, 3.61.
ꢀtri¯uoromethyl)ethyl]acetamide ꢀ9b). This compound
was obtained as colourless crystals )7.48 g; 98%), mp
1
119±1208C; IR )KBr) 3340; 1679; 1171; 1111 cm21; H
Hydrochloride )10b´HCl): mp 213±2148C; IR )KBr) 2541;
1599; 1241 cm21 1H NMR )200 MHz, DMSO-d6 and
;
NMR )400 MHz, CDCl3): 6.97 )1H, s); 6.93 )1H, d,
Jˆ8.2 Hz); 6.83 )1H, d, Jˆ8.2 Hz); 6.00 )1H, d,
Jˆ1.4 Hz); 5.99 )1H, d, Jˆ1.4 Hz); 5.86 )1H, bs); 4.09
)1H, dd, Jˆ14.8, 5.3 Hz); 3.89 )1H, ddq, Jˆ14.8, 5.3,
1.2 Hz); 3.33 )3H, s); 1.99 )3H, s); 13C NMR )100.6 MHz,
CDCl3): d: 8.51 )1H, d, Jˆ8.8 Hz); 8.16 )1H, d,
Jˆ15.8 Hz); 8.05±7.96 )2H, m); 7.77 )1H, d, Jˆ15.8 Hz);
7.50±7.30 )3H, m); 7.25 )1H, s); 4.49 )1H, d, Jˆ16.1 Hz);
4.25 )1H, d, Jˆ16.1 Hz); 4.02 )3H, s); 3.39 )3H, s). Anal.
Calcd for C20H18ClF4NO2 )415.81): C, 57.77; H, 4.36; Cl,
8.53; N, 3.37. Found: C, 57.54; H, 4.31; Cl, 8.57; N, 3.40.
1
CDCl3): 170.0; 148.2; 148.1; 126.8; 124.7 )q, JCFˆ
2
288.0 Hz); 121.1; 108.2; 107.8; 101.4; 80.3 )q, JCFˆ
26.6 Hz); 52.2; 40.7; 23.1. Anal. Calcd for C13H14F3NO4
)305.25): C, 51.15; H, 4.62; N, 4.59. Found: C, 51.38; H,
4.67; N, 4.69.
3.5.3. 4,6-Dimethoxy-4-tri¯uoromethyl-1-[4-ꢀtri¯uoro-
methyl)styryl]-3,4-dihydroisoquinoline
compound was obtained as beige crystals )72%), mp 87±
888C; IR )KBr) 1608; 1325; 1166 cm21 1H NMR
ꢀ10c).
This
;
3.5. General procedure for synthesis of 1-styryl- and
1-methyl-4-methoxy-4-tri¯uoromethyl-3,4-dihydroiso-
quinolines ꢀ10,11)
)400 MHz, CDCl3): 7.69 )1H, d, Jˆ8.7 Hz); 7.67±7.61
)4H,m); 7.48 )1H, d, Jˆ15.9 Hz); 7.30 )1H, d,
Jˆ15.9 Hz); 7.25 )1H, d, Jˆ2.4 Hz); 7.04 )1H, dd, Jˆ8.7,
2.4 Hz); 4.28 )1H, d, Jˆ17.5 Hz); 4.18 )1H, d, Jˆ17.5 Hz);
3.91 )3H, s); 3.33 )3H, s); 13C NMR )100.6 MHz, CDCl3):
161.9; 161.4; 139.7; 135.1; 132.5; 130.5 )q, 2JCFˆ32.4 Hz);
A mixture of amide 8 or 9 )10 mmol) and phosphorus
oxychloride )4.5 ml, 7.67 g, 50 mmol) was heated for 16 h
at90 8C. The mixture was poured into ice-water )40 ml) and
the pH adjusted to 11 by addition of aqueous ammonium
hydroxide solution )28%). The aqueous layer was extracted
with ethyl acetate )3£30 ml). The combined organic layers
were dried )MgSO4) and evaporated. The residue was
recrystallised from hexane )10b±e) or acetonitrile )11a,b)
to afford the title compounds. Hydrochloride salts were
obtained by addition of an equivalent amount of hydro-
chloric acid in ethanolic solution )25.3 g/100 ml) to a solu-
tion of the bases in isopropyl ether ),5 ml/mmol). The
hydrochloride salts were recrystallised from ethanol.
1
128.0; 127.5; 126.3; 125.4 )q, JCFˆ293.8 Hz); 125.8 )q,
1
3JCFˆ3.8 Hz); 124.0 )q, JCFˆ272.0 Hz); 122.8; 114.9;
2
112.9; 75.1 )q, JCFˆ27.8 Hz); 55.6; 52.6; 49.6. Anal.
Calcd for C21H17F6NO2 )429.36): C, 58.75; H, 3.99; N,
3.26. Found: C, 58.58; H, 3.95; N, 3.30.
Hydrochloride )10c´HCl): mp 234±2358C; IR )KBr) 1599;
1423; 1252 cm21; 1H NMR )200 MHz, DMSO-d6): d: 8.56
)1H, d, Jˆ8.9 Hz); 8.31 )1H, d, Jˆ16.1 Hz); 8.13 )2H, d,
Jˆ8.2 Hz); 7.94 )1H, d, Jˆ16.1 Hz); 7.90 )2H, d,
Jˆ8.2 Hz); 7.43 )1H, dd, Jˆ8.9, 2.4 Hz); 7.26 )1H, bs);
4.54 )1H, d, Jˆ16.5 Hz); 4.27 )1H, d, Jˆ16.5 Hz); 4.03
)3H, s); 3.40 )3H, s). Anal. Calcd for C21H18ClF6NO2
)465.82): C, 54.15; H, 3.89; Cl, 7.61; N, 3.01. Found: C,
53.94; H, 3.86; Cl, 7.57; N, 2.99.
3.5.1. 4,6-Dimethoxy-1-styryl-4-tri¯uoromethyl-3,4-di-
hydroisoquinoline hydrochloride ꢀ10a´HCl). This
compound was obtained as pale yellow crystals )53%),
mp 188±1898C; IR )KBr) 3435; 1508; 1477 cm21 1H
;
NMR )400 MHz, DMSO-d6 and CDCl3): 8.49 )1H, d,
Jˆ8.9 Hz); 8.22 )1H, m); 7.88 )2H, dd, Jˆ7.6, 1.8 Hz);
7.73 )1H, d, Jˆ16.1 Hz); 7.53 )3H, m); 7.35 )1H, dd,
Jˆ8.9, 2.6 Hz); 7.29 )1H, d, Jˆ2.6 Hz); 6.60 )1H, bs);
4.42 )1H, d, Jˆ16.0 Hz); 4.26 )1H, d, Jˆ16.0 Hz); 4.04
)3H, s); 3.42 )3H, s); 13C NMR )100.6 MHz, DMSO-d6
and CDCl3): 166.9; 166.6; 149.6; 135.7; 134.2; 133.7;
3.5.4. 4,6-Dimethoxy-1-ꢀ4-nitrostyryl)-4-tri¯uoromethyl-
3,4-dihydroisoquinoline ꢀ10d). This compound was
obtained as colourless crystals )63%), mp 146±1478C; IR
1
)KBr) 1612; 1514; 1313; 1178 cm21; H NMR )200 MHz,
CDCl3): 8.24 )2H, dd, Jˆ8.8, 1.9 Hz); 7.75±7.65 )3H, m);
7.53 )1H, d, Jˆ15.9 Hz); 7.37 )1H, d, Jˆ15.9 Hz); 7.25

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L. Poszavacz, G. Simig / Tetrahedron 57 /2001) 8573±8580
8578
)1H, d, Jˆ2.6 Hz); 7.06 )1H, dd, Jˆ8.3, 2.6 Hz); 4.32 )1H,
d, Jˆ17.6 Hz); 4.18 )1H, d, Jˆ17.6 Hz); 3.92 )3H, s); 3.34
)3H, s). Anal. Calcd for C20H17F3N2O4 )406.36): C, 59.11;
H, 4.22; N, 6.89. Found: C, 58.87; H, 4.24; N, 6.83.
was obtained as colourless crystals )1.08 g; 75%), mp
1
203±2048C; IR )KBr) 1606; 1286; 1173 cm21; H NMR
)400 MHz, CDCl3): 7.13 )1H, q, Jˆ0.9 Hz); 7.07 )1H, s);
6.08 )1H, d, Jˆ0.9 Hz); 6.06 )1H, d, Jˆ1.3 Hz); 4.01 )1H,
ddd, Jˆ16.8, 3.0, 1.5 Hz); 4.00 )1H, dd, Jˆ16.8, 1.5 Hz);
3.24 )3H, s); 2.37 )3H, t, Jˆ1.7 Hz); 13C NMR )100.6 MHz,
Hydrochloride )10d´HCl): mp 245±2468C; IR )KBr) 1599;
1345; 1250; 1181 cm21; 1H NMR )200 MHz, DMSO-d6 and
CDCl3): d: 8.48 )1H, d, Jˆ8.8 Hz); 8.36 )1H, d, Jˆ8.8 Hz);
8.24±8.06 )4H, m); 7.97 )1H, d, Jˆ16.1 Hz); 7.40 )1H, dd,
Jˆ8.8, 2.2 Hz); 7.25 )1H, s); 4.51 )1H, d, Jˆ16.5 Hz); 4.02
)1H, d, Jˆ16.5 Hz); 4.02 )3H, s); 3.38 )3H, s). Anal. Calcd
for C20H18ClF3N2O4 )442.82): C, 54.25; H, 4.10; Cl, 8.01;
N, 6.33 Found: C, 54.14; H, 4.08; Cl, 8.07; N, 6.23.
1
CDCl3): 162.4; 149.8; 148.9; 125.2 )q, JCFˆ287.3 Hz);
3
125.1; 124.5; 107.3 )q, JCFˆ1.9 Hz); 106.4; 102.0; 75.2
2
)q, JCFˆ27.6 Hz); 52.1; 49.1; 23.6. Anal. Calcd for
C13H12F3NO3 )287.24): C, 54.36; H, 4.21; N, 4.88. Found:
C, 54.19; H, 4.27; N, 4.79.
Hydrochloride )11b´HCl): mp 209±2108C; IR )KBr) 2523;
1501; 1182; 1120 cm21; 1H NMR )400 MHz, DMSO-d6 and
CDCl3): d: 7.81 )1H, s); 7.29 )1H, s); 6.36 )1H, d,
Jˆ0.8 Hz); 6.33 )1H, d, Jˆ0.8 Hz); 4.40 )1H, d,
Jˆ16.6 Hz); 4.14 )1H, dd, Jˆ16.6, 0.8 Hz); 3.31 )3H, s);
2.84 )3H, d, Jˆ0.6 Hz). Anal. Calcd for C13H13ClF3NO3
)323.70): C, 48.24; H, 4.05; Cl, 10.95; N, 4.33. Found: C,
48.54; H, 4.02; Cl, 10.94; N, 4.36.
3.5.5. 4-Methoxy-6,7-methylenedioxy-4-tri¯uoromethyl-
1-[4-ꢀtri¯uoromethyl)styryl]-3,4-dihydroisoquinoline
ꢀ10e). This compound was obtained as beige crystals )55%),
1
mp 87±888C; IR )KBr) 1579; 1389; 1167 cm21; H NMR
)400 MHz, CDCl3): 7.70±7.60 )4H, m); 7.46 )1H, d,
Jˆ15.9 Hz); 7.24 )1H, d, Jˆ15.9 Hz); 7.19 )1H, s); 7.18
)1H, s); 6.15 )1H, d, Jˆ1.3 Hz); 6.09 )1H, d, Jˆ1.3 Hz);
4.26 )1H, d, Jˆ17.7 Hz); 4.16 )1H, d, Jˆ17.7 Hz); 3.30
)3H, s); 13C NMR )100.6 MHz, CDCl3): 161.0; 150.1;
3.6. General procedure for synthesis of 1-methyl-4-
ꢀtri¯uoromethyl)isoquinolines ꢀ12)
2
148.9; 139.5; 135.4; 130.6 )q, JCFˆ32.4 Hz); 127.5;
3
1
126.2; 125.7 )q, JCFˆ5.4 Hz); 125.6; 125.3 )q, JCFˆ
A mixture of 3,4-dihydroisoquinolines 11 )10 mmol) and
potassium hydroxide )0.84 g, 15 mmol) in 2-propanol
)20 ml) was stirred for 2 h at 508C. The solventwas evapo-
rated and the residue was triturated with water )10 ml). The
crystalline precipitate was ®ltered and recrystallised from
petroleum ether )bp 80±1008C).
1
287.3 Hz); 124.5; 124.0 )q, JCFˆ272.0 Hz); 107.6; 106.4;
2
102.1; 75.2 )q, JCFˆ27.5 Hz); 52.4; 49.6. Anal. Calcd for
C21H15F6NO3 )443.35): C, 56.89; H, 3.41; N, 3.16. Found:
C, 56.71; H, 3.39; N, 3.22.
Hydrochloride )10e´HCl): mp 248±2508C; IR )KBr) 1623;
1
1514; 1394; 1325; 1171; 1126 cm21; H NMR )400 MHz,
3.6.1. 6-Methoxy-1-methyl-4-ꢀtri¯uoromethyl)isoquino-
line ꢀ12a). This compound was obtained as colourless crys-
tals )2.05 g; 85%), mp 95±968C; IR )KBr) 1624; 1256;
DMSO-d6): d: 8.15±8.05 )4H, m); 7.90±7.80 )3H, m); 7.32
)1H, m); 6.37 )1H, d, Jˆ0.9 Hz); 6.34 )1H, d, Jˆ0.9 Hz);
4.45 )1H, d, Jˆ17.0 Hz); 4.24 )1H, d, Jˆ17.0 Hz); 3.60
)1H, bs); 3.35 )3H, s). Anal. Calcd for C21H16ClF6NO3
)479.81): C, 52.57; H, 3.36; Cl, 7.39; N, 2.92. Found: C,
52.61; H, 3.38; Cl, 7.38; N, 2.94.
1
1165; 1126 cm21; H NMR )250 MHz, CDCl3): 8.64 )1H,
d, Jˆ0.7 Hz); 8.10 )1H, d, Jˆ9.0 Hz); 7.35±7.20 )2H, m);
3.98 )3H, s); 2.96 )3H, s); 13C NMR )62.9 MHz, CDCl3):
3
162.7; 161.5; 140.8 )q, JCFˆ6.7 Hz); 133.7; 128.0; 124.7
)q, 1JCFˆ272.4 Hz); 122.6; 120.2; 118.0 )q, 2JCFˆ28.9 Hz);
102.1; 55.4; 22.8. Anal. Calcd for C12H10F3NO )241.21): C,
59.75; H, 4.18; N, 5.81. Found: C, 59.57; H, 4.13; N, 5.76.
3.5.6. 4,6-Dimethoxy-1-methyl-4-tri¯uoromethyl-3,4-di-
hydroisoquinoline ꢀ11a). This compound was obtained as
colourless crystals )81%), mp 203±2048C; IR )KBr) 1609;
1247; 1178 cm21; 1H NMR )250 MHz, CDCl3): 7.56 )1H, d,
Jˆ8.7 Hz); 7.19 )1H, dd, Jˆ2.6, 0.8 Hz); 7.00 )1H, dd,
Jˆ8.7, 2.6 Hz); 4.12 )1H, dq, Jˆ17.5, 1.5 Hz); 4.02 )1H,
dq, Jˆ17.5, 1.5 Hz); 3.88 )3H, s); 3.27 )3H, s); 2.39 )3H, t,
Jˆ1.7 Hz); 13C NMR )62.9 MHz, CDCl3): 162.7; 161.5;
3.6.2. 1-Methyl-6,7-methylenedioxy-4-ꢀtri¯uoromethyl)-
isoquinoline ꢀ12b). This compound was obtained as colour-
less crystals )2.30 g; 90%), mp 139±1418C; IR )KBr) 1477;
1
1167; 1112 cm21; H NMR )200 MHz, CDCl3): 8.58 )1H,
s); 7.44 )1H, s); 7.40 )1H, q, Jˆ1.8 Hz); 6.17 )2H, s); 2.91
1
131.2; 127.8; 125.1 )q, JCFˆ287.2 Hz); 123.2; 114.7;
)3H, s); 13C NMR )100.6 MHz, CDCl3): 161.1; 151.8;
2
112.4; 74.9 )q, JCFˆ27.9 Hz); 55.3; 52.1; 48.9; 23.0.
3
1
148.6; 139.3 )q, JCFˆ6.5 Hz); 130.1; 124.7 )q, JCFˆ
Anal. Calcd for C13H14F3NO2 )273.25): C, 57.14; H, 5.16;
N, 5.13. Found: C, 57.27; H, 5.26; N, 5.11.
2
273.1 Hz); 124.6; 118.6 )q, JCFˆ30.5 Hz); 102.2; 100.6;
23.3. Anal. Calcd for C12H8F3NO2 )255.196): C, 56.48; H,
3.16; N, 5.49. Found: C, 56.33; H, 3.14; N, 5.45.
Hydrochloride )11a´HCl): mp 209±2108C; IR )KBr) 2496;
1608; 1254; 1178 cm21; 1H NMR )250 MHz, DMSO-d6 and
CDCl3): d: 8.25 )1H, d, Jˆ8.8 Hz); 7.40 )1H, dd, Jˆ8.8,
2.5 Hz); 7.19 )1H, d, Jˆ2.5 Hz); 4.44 )1H, d, Jˆ16.5 Hz);
4.18 )1H, d, Jˆ16.5 Hz); 3.99 )3H, s); 3.35 )3H, s); 2.89
)3H, s). Anal. Calcd for C13H15ClF3NO2 )309.72): C, 50.42;
H, 4.88; Cl, 11.45; N, 4.52. Found: C, 50.25; H, 4.85; Cl,
11.46; N, 4.48.
3.7. General procedure for synthesis of 1-styryl-4-
ꢀtri¯uoromethyl)isoquinolines ꢀ13)
Method A )starting from compounds 10): A mixture of 4-
methoxy-1-styryl-4-tri¯uoromethyl-3,4-dihydroisoquinoline
hydrochlorides )10´HCl, 3 mmol) and potassium hydroxide
)0.42 g, 7.5 mmol) in methanol )10 ml) was stirred for 2 h at
ambient temperature. The solvent was evaporated and the
residue was triturated with water )10 ml), ®ltered, washed
3.5.7. 4-Methoxy-1-methyl-6,7-methylenedioxy-4-tri¯uoro-
methyl-3,4-dihydroisoquinoline ꢀ11b). This compound

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L. Poszavacz, G. Simig / Tetrahedron 57 /2001) 8573±8580
8579
with ice-cold ethanol )2£4 ml) and recrystallised from
)4%); 316 )9%); 304 )10%); 303 )34%); 252 )8%). Anal.
Calcd for C19H13F4NO )347.32): C, 65.71; H, 3.77; N, 4.03.
Found: C, 65.84; H, 3.79; N, 4.08.
chloroform.
Method B )starting from compounds 11): A mixture of
4-methoxy-1-methyl-4-tri¯uoromethyl-3,4-dihydroisoquino-
line )11, 10 mmol), an aromatic aldehyde )11 mmol, see
Scheme 3) and acetic anhydride )1.33 g, 13 mmol) was
heated for 16 h at 1008C. After cooling the crystalline pre-
cipitate was ®ltered washed with ice-cold ethanol )2£4 ml)
and recrystallised from chloroform.
Hydrochloride )13b´HCl): mp 189±1908C; IR )KBr) 3437;
1
1615; 1228; 1162 cm21; H NMR )250 MHz, DMSO-d6):
8.95 )1H, d, Jˆ9.5 Hz); 8.77 )1H, s); 8.29 )1H, d, Jˆ
15.6 Hz); 8.18 )1H, d, Jˆ15.6 Hz); 8.04 )1H, d, Jˆ
5.6 Hz); 8.00 )1H, d, Jˆ5.6 Hz); 7.56 )1H, dd, Jˆ9.5 Hz;
Jˆ2.4 Hz); 7.33 )2H, t, Jˆ8.8 Hz); 7.29 )1H, s); 4.02 )3H,
s). Anal. Calcd for C19H14ClF4NO )383.77): C, 59.46; H,
3.68; Cl, 9.24; N, 3.65. Found: C, 59.19; H, 3.72; Cl, 9.10;
N, 3.58.
Method C )starting from compounds 12): A mixture of
1-methyl-4-)tri¯uoromethyl)isoquinoline )12, 10 mmol),
an aromatic aldehyde )11 mmol, see Scheme 3) and acetic
anhydride )1.33 g, 13 mmol) was heated for 16 h at 1008C.
After cooling the crystalline precipitate was ®ltered and
washed with ice-cold ethanol )2£4 ml) and recrystallised
from chloroform.
3.7.3.
6-Methoxy-4-ꢀtri¯uoromethyl)-1-[ꢀ4-tri¯uoro-
methyl)styryl]isoquinoline ꢀ13c). This compound was
obtained as light yellow crystals )90, 62, 70%), mp 160±
1
1618C; IR )KBr) 1620; 1409; 1324; 1121 cm21; H NMR
)250 MHz, CDCl3): 8.80 )1H, s); 8.34 )1H, d, Jˆ9.7 Hz);
8.08 )1H, d, Jˆ15.6 Hz); 7.98 )1H, d, Jˆ15.6 Hz); 7.78
)2H, d, Jˆ8.3 Hz); 7.68 )2H, d, Jˆ8.3 Hz); 7.37 )1H, s);
7.35 )1H, dd, Jˆ9.7, 2.5 Hz); 4.00 )3H, s); 13C NMR
Hydrochloride salts were obtained by addition of an equiva-
lent amount of hydrochloric acid in ethanolic solution
)25.3 g/100 ml) to a solution of the bases in isopropyl
ether ),5 ml/mmol). The hydrochloride salts were
recrystallised from ethanol.
3
)62.9 MHz, CDCl3): 161.7; 157.2; 141.4 )q, JCFˆ6.5 Hz);
139.8; 136.5; 135.0; 130.1 )q, 2JCFˆ32.5 Hz); 127.8; 126.8;
3
1
125.8 )q, JCFˆ4.6 Hz); 124.8 )q, JCFˆ271.8 Hz); 124.5;
1
Compounds 13 were prepared by all the three methods, the
yields are indicated accordingly.
124.2 )q, JCFˆ271.0 Hz); 122.6; 120.8; 118.5 )q,
2JCFˆ27.8 Hz); 102.1; 55.6; MS: 397 )57%); 396 )100%);
382 )11%); 378 )9%); 366 )12%); 354 )10%); 353 )36%);
328 )6%); 285 )11%); 252 )16%); 69 )8%). Anal. Calcd for
C20H13F6NO )397.32): C, 60.46; H, 3.30; N, 3.53. Found: C,
60.70; H, 3.27; N, 3.63.
3.7.1. 6-Methoxy-1-styryl-4-ꢀtri¯uoromethyl)isoquino-
line ꢀ13a). This compound was obtained as light yellow
crystals )95, 65, 60%), mp 202±2038C; IR )KBr) 1619;
;
1411; 1318; 1221; 1100 cm21 1H NMR )200 MHz,
CDCl3): 8.79 )1H, s); 8.36 )1H, d, Jˆ9.5 Hz); 8.07 )1H, d,
Jˆ15.8 Hz); 7.92 )1H, d, Jˆ15.8 Hz); 7.75±7.65 )2H, m);
7.45±7.30 )5H, m); 3.99 )3H, s); 13C NMR )50.3 MHz,
Hydrochloride )13c´HCl): mp 189±1908C; IR )KBr) 3433;
1
1613; 1319; 1132 cm21; H NMR )250 MHz, DMSO-d6):
8.92 )1H, d, Jˆ9.5 Hz); 8.83 )1H, s); 8.47 )1H, d,
Jˆ15.5 Hz); 8.20±8.13 )3H, s); 7.81 )2H, d, Jˆ8.2 Hz);
7.54 )1H, dd, Jˆ9.5, 2.4 Hz); 7.29 )1H, s); 4.00 )3H, s).
Anal. Calcd for C20H14ClF6NO )433.78): C, 55.38; H,
3.25; Cl, 8.17; N, 3.23. Found: C, 55.62; H, 3.37; Cl,
8.29; N, 3.19.
3
CDCl3): 161.7; 157.8; 141.1 )q, JCFˆ6.5 Hz); 138.7;
136.4; 135.0; 129.3; 128.9; 127.7; 127.1; 124.8 )q,
2
1JCFˆ273.1 Hz); 121.8; 120.5; 117.8 )q, JCFˆ30.1 Hz);
102.1; 55.6; MS: 329 )37%); 328 )100%); 314 )7%); 310
)3%); 298 )8%); 286 )10%); 285 )37%); 252 )7%). Anal.
Calcd for C19H14F3NO )329.32): C, 69.20; H, 4.28; N, 4.25.
Found: C, 69.02; H, 4.25; N, 4.20.
3.7.4. 6-Methoxy-1-ꢀ4-nitrostyryl)-4-ꢀtri¯uoromethyl)-
isoquinoline ꢀ13d). This compound was obtained as light
yellow crystals )92, 74, 73%) mp 223±2248C; IR )KBr)
Hydrochloride )10e´HCl): mp 189±1908C; IR )KBr) 1618;
1
1
1240 cm21; H NMR )250 MHz, DMSO-d6): 8.92 )1H, d,
1619; 1327; 1106 cm21; H NMR )400 MHz, DMSO-d6):
Jˆ9.4 Hz); 8.76 )1H, s); 8.28 )1H, d, Jˆ15.7 Hz); 8.15 )1H,
d, Jˆ15.7 Hz); 7.93±7.89 )2H, m); 7.58 )1H, d, Jˆ9.4 Hz);
7.50±7.40 )3H, m); 7.32 )1H, s); 4.00 )3H, s). Anal. Calcd
for C19H15ClF3NO )365.78): C, 62.39; H, 4.13; Cl, 9.69; N,
3.83. Found: C, 62.21; H, 4.17; Cl, 9.60; N, 3.86.
8.92 )1H, d, Jˆ9.3 Hz); 8.87 )1H, s); 8.56 )1H, d,
Jˆ15.3 Hz); 8.29 )2H, d, Jˆ8.7 Hz); 8.21 )2H, d,
Jˆ8.7 Hz); 8.18 )1H, d, Jˆ15.3 Hz); 7.55 )1H, d,
Jˆ9.3 Hz); 7.30 )1H, s); 4.00 )3H, s).; 13C NMR
)50.3 MHz, CDCl3): 161.9; 157.4; 147.5; 142.8; 135.7;
1
134.2; 129.3; 128.7; 127.0; 126.2 )q, JCFˆ 274.3 Hz);
2
3.7.2. 1-ꢀ4-Fluorostyryl)-6-methoxy-4-ꢀtri¯uoromethyl)-
isoquinoline ꢀ13b). This compound was obtained as light
yellow crystals )93, 64, 63%), mp 187±1888C; IR )KBr)
124.1; 121.8; 120.7; 116.4 )q, JCFˆ32.7 Hz); 101.7;
55.9.; MS: 374 )100%); 373 )99%); 359 )12%); 355 )7%);
344 )12%); 343 )28%); 328 )27%); 327 )68%); 326 )15%);
313 )15%); 285 )29%); 284 )23%); 283 )16%); 252 )26%);
216 )12%); 215 )19%). Anal. Calcd for C19H13F3N2O3
)374.32): C, 60.97; H, 3.50; N, 7.48. Found: C, 60.78; H,
3.46; N, 7.46.
1
1618; 1510; 1321; 1275; 1130 cm21; H NMR )250 MHz,
CDCl3): 8.77 )1H, s); 8.31 )1H, d, Jˆ9.1 Hz); 8.01 )1H, d,
Jˆ15.5 Hz); 7.81 )1H, d, Jˆ15.5 Hz); 7.70±7.63 )2H, m);
7.35±7.29 )2H, m); 7.11 )2H, t, Jˆ8.7 Hz); 3.98 )3H, s); 13C
1
NMR )62.9 MHz, CDCl3): 165.2; 161.5; 159.5 )d, JCFˆ
3
221.5 Hz); 141.3 )q, JCFˆ6.6 Hz); 136.9; 134.8; 132.6;
Hydrochloride )13d´HCl): mp . 2508C; IR )KBr) 2440;
1
1
129.3; 129.2; 126.8; 124.8 )q, JCFˆ273.6 Hz); 121.8;
1646; 1345; 1262 cm21; H NMR )200 MHz, DMSO-d6):
2
2
120.3; 117.7 )q, JCFˆ29.3 Hz); 115.8 )d, JCFˆ21.0 Hz);
102.1; 55.4; MS: 347 )34%); 346 )100%); 332 )10%); 328
8.96 )1H, d, Jˆ9.5 Hz); 8.86 )1H, s); 8.57 )1H, d,
Jˆ15.4 Hz); 8.36±8.14 )5H, m); 7.57 )1H, dd, Jˆ9.5,

 Â
L. Poszavacz, G. Simig / Tetrahedron 57 /2001) 8573±8580
8580
2.2 Hz); 7.30 )1H, s); 3.85 )3H, s). Anal. Calcd for
C19H14ClF3N2O3 )410.78): C, 55.56; H, 3.44; Cl, 8.63; N,
6.82. Found: C, 55.87; H, 3.29; Cl, 8.56; N, 6.84.
d, Jˆ15.9 Hz); 2.75 )3H, s); 13C NMR )100.6 MHz, DMSO-
d6): 174.3; 166.1; 137.3; 134.5; 117.4; 116.8; 114.2; 69.2 )q,
2JCFˆ29.0 Hz); 45.7; 19.4. Anal. Calcd for C11H11ClF3NO2
)281.66): C, 46.91; H, 3.94; Cl, 12.59; N, 4.97. Found: C,
46.65; H, 3.90; Cl, 12.64; N, 4.94.
3.7.5. 6,7-Methylenedioxy-4-ꢀtri¯uoromethyl)-1-[ꢀ4-tri-
¯uoromethyl)styryl]isoquinoline ꢀ13e). This compound
was obtained as light yellow crystals )92, 64, 68%), mp
3.7.7. 6-Hydroxy-1-methyl-4-ꢀtri¯uoromethyl)isoquino-
line ꢀ15). A mixture of dihydroisoquinoline )11a, 1.37 g,
5 mmol) and concentrated sulphuric acid )6 ml) was heated
with stirring for 6 h at 1108C. After cooling to room
temperature the pH of the mixture was adjusted to 11 by
addition of aqueous ammonium hydroxide solution )28%).
The mixture was extracted with ethyl acetate )3£40 ml).
The combined organic layer were dried )MgSO4) and
evaporated. The residue was puri®ed by column chromato-
graphy )eluent: toluene/ethyl acetateˆ95:5) to give 15
)0.72 g, 63%), mp 243±2448C; IR )KBr) 1609; 1515;
1
180±1828C; IR )KBr) 1615; 1478; 1324; 1104 cm21; H
NMR )200 MHz, CDCl3): 8.72 )1H, s); 8.04 )1H, d,
Jˆ15.4 Hz); 7.84 )1H, d, Jˆ15.4 Hz); 7.76 )2H, s); 7.69
)2H, s); 7.66 )1H, s); 7.43 )1H, q, Jˆ1.8 Hz); 6.20 )2H,
s); 13C NMR )100.6 MHz, CDCl3): 155.8; 152.0; 149.0;
4
139.8 )q, JCFˆ1.5 Hz); 136.7; 136.2; 131.5; 130.6 )q,
3
2JCFˆ32.8 Hz); 127.7; 125.8 )q, JCFˆ3.8 Hz); 124.6;
1
1
124.6 )q, JCFˆ273.1 Hz); 124.0 )q, JCFˆ272.0 Hz);
3
124.0; 102.4; 101.1; 100.5 )q, JCFˆ2.7 Hz); MS: 411
)37%); 410 )100%); 392 )10%); 382 )13%); 382 )2%);
380 )2%); 353 )11%); 352 )7%); 284 )7%); 283 )7%); 266
)28%); 240 )3%); 171 )16%). Anal. Calcd for C20H11F6NO2
)411.30): C, 58.40; H, 2.70; N, 3.41. Found: C, 58.22; H,
2.73; N, 3.35.
1
1248; 1126 cm21; H NMR )250 MHz, DMSO-d6): 10.85
)1H, bs); 8.58 )1H, s); 8.26 )1H, d, Jˆ9.0 Hz); 7.32 )1H, dd,
Jˆ9.0, 2.2 Hz); 7.28 )1H, t, Jˆ2.0 Hz); 2.89 )3H, s); 13C
NMR )62.9 MHz, DMSO-d6 and CDCl3): 163.3; 160.5;
3
1
140.4 )q, JCFˆ6.7 Hz); 132.9; 129.5; 124.9 )q, JCFˆ
2
273.5 Hz); 121.3; 120.4; 116.0 )q, JCFˆ29.3 Hz); 104.4;
Hydrochloride )13e´HCl): mp 259±2608C; IR )KBr) 1630;
1482; 1320; 1180; 1134 cm21; 1H NMR )400 MHz, DMSO-
d6): 8.73 )1H, s); 8.41 )1H, s); 8.38 )1H, d, Jˆ15.4 Hz); 8.16
)2H, d, Jˆ8.2 Hz); 8.11 )1H, d, Jˆ15.4 Hz); 7.80 )2H, d,
Jˆ8.2 Hz); 7.34 )1H, q, Jˆ1.4 Hz); 6.36 )2H, s). Anal.
Calcd for C20H12ClF6NO2 )447.77): C, 53.65; H, 2.70; Cl,
7.92; N, 3.13. Found: C, 53.82; H, 2.63; Cl, 7.87; N, 3.16.
22.7. Anal. Calcd for C11H8F3NO )227.19): C, 58.16; H,
3.55; N, 6.17. Found: C, 57.92; H, 3.65; N, 6.09.
References
 Â
1. Balogh, Gy.; Doman, I.; Blasko, G.; Simig, Gy.; Kovacs, E.;
 Â
Egyed, I.; Gacsalyi, I.; Bilkei-Gorzo, A.; Pallagi, K.;
3.7.6. 4,6-Dihydroxy-1-methyl-4-tri¯uoromethyl-3,4-di-
hydroisoquinoline hydrochloride ꢀ14´HCl). A mixture of
4,6-dimethoxy-1-methyl-4-tri¯uoromethyl-3,4-dihydroiso-
quinoline )11a, 1.37 g, 5 mmol) and a solution )w/w 30%)
of hydrobromic acid in glacial acetic acid )20 ml) was
re¯uxed for 6 h. After cooling to room temperature the pH
of the mixture was adjusted to 11 by addition of aqueous
ammonium hydroxide solution )28%). It was extracted with
ethyl acetate )3£40 ml). The combined organic layer were
dried )MgSO4) and evaporated. The residue was dissolved
in ether )20 ml) and an equivalent amount of hydrochloric
acid solution in 2-propanol )25.3 g/100 ml) was added. The
crystalline product was ®ltered to give 14 hydrochloride
)0.81 g, 57%) as colourless crystals, mp 242±2438C; IR
 Â
Szemeredi, K.; Kazo, K. EP 680,953 )to EGIS Pharmaceuticals
Ltd., ®led in 1995); Chem. Abstr., 1996, 124, 175859t.
 Â
2. Poszavacz, L.; Simig, Gy. J. Heterocycl. Chem. 2000, 37, 343.
3. Fitton, A. O.; Frost, J. R.; Zakaria, M. M.; Andrew, G. J. Chem.
Soc., Chem. Commun. 1973, 889.
4. Goszczynski, S.; Kopczynski, T. J. Org. Chem. 1973, 33, 1245.
5. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543.
6. Shaw, B. D.; Wagstaff, E. A. J. Org. Chem. 1949, 14, 650.
7. Tabb, C.; Wislon, J.; West, M.; Brauder, G.; Goan, J. C.; Cook,
C.; Fain, J.; Franklin, E.; Meyers, A. J. Org. Chem. 1957, 22,
683.
8. Kametani, T.; Fukumoto, K. In Isoquinoline: Synthetic and
Natural Sources of the Isoquinoline Nucleus; Part One, Grethe,
G., Ed.; Wiley: New York, 1981; pp. 162±163.
1
)KBr) 1612; 1567; 1300; 1240 cm21; H NMR )400 MHz,
D2O): 8.01 )1H, d, Jˆ8.9 Hz); 7.27 )1H, d, Jˆ2.4 Hz); 7.08
)1H, dd, Jˆ8.9, 2.4 Hz); 4.29 )1H, d, Jˆ15.9 Hz); 3.97 )1H,