Synthesis of new trans-2-benzyl-3-(furan-2-yl)-4-substituted-1,2,3,4- tetrahydroisoquinolinones

Article abstract of DOI:10.3390/11060403

The reaction of homophthalic anhydride and N-(furan-2-yl-methylidene)- benzylamine in different solvents and varying temperatures was studied in detail. Mixtures of the expected trans- and cis-1,2,3,4-tetrahydroisoquinoline- 4-carboxylic acids trans-5 and

Full text of DOI:10.3390/11060403

Molecules 2006, 11, 403-414
molecules
ISSN 1420-3049
http://www.mdpi.org
Full Paper
Synthesis of New trans-2-Benzyl-3-(furan-2-yl)-4-substituted-
1,2,3,4-tetrahydroisoquinolinones
Meglena I. Kandinska 1, Ivan D. Kozekov 2 and Mariana D. Palamareva 1,*
1 Department of Chemistry, University of Sofia, 1 James Bouchier Avenue, Sofia 1164, Bulgaria
2 Vanderbilt University, Chemistry Department, P. O. Box 1822-B, Nashville, TN 37235, USA
* Author to whom correspondence should be addressed; e-mail mpalamareva@chem.uni-sofia.bg
Received: 10 May 2006 / Accepted: 8 June 2006 / Published: 12 June 2006
Abstract: The reaction of homophthalic anhydride and N-(furan-2-yl-methylidene)-
benzylamine in different solvents and varying temperatures was studied in detail. Mixtures
of the expected trans- and cis-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acids trans-5 and
cis-5, alongwith by-products 6 and 7 were obtained in dichloroethane or benzene. In
pyridine, used for the first time, the reaction became completely diastereoselective, giving
only the trans isomer. The carboxylic acid group of trans-5 was transformed in four steps
into cyclic aminomethyl groups which yielded various new tetrahydroisoquinolinones trans-
11a-g, incorporating both a known fragment of pharmacological interest and various
pharmacophoric substituents.
Keywords: Homophthalic anhydride, imine, tetrahydroisoquinolinones, stereochemistry.
Introduction
Substituted 1,2,3,4-tetrahydroisoquinolines are important because of their occurrence in nature [1,2]
and their pharmacological properties [3-6]. Several methods have been described for preparation of
tetrahydroisoquinolines [7-20]. The reaction between homophthalic anhydride and imines, developed
in our laboratory [15], is nowadays a well known method for an one step preparation of acids of type 1
having two stereogenic centers and thus cis and trans forms if R1 is different from R2 [15-18, 20-22].
Depending of the conditions (solvent, temperature and catalyst if any), the reaction leads to mixtures

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of cis- and trans-isomers or to one of these isomers [15-18, 21-26]. In some cases side reactions take
place and by-products are isolated [20-22].
N
O
COOH
R2
O
R1
N
N
N
O
R
O
O
O
1
2
3
4
This paper continues our attempts [21,22] to further outline the scope and limitations of the
reaction between homophthalic anhydride and imines and to study its stereochemistry. The latter is of
interest because the effect of reaction conditions cannot be predicted in advance. Moreover, attention
was paid to the transformation of the products of type 1 into various compounds of type 2 having a
cyclic aminomethyl group in position 4 of the tetrahydroisoquinolinone ring. The presence of the
fragment given in bold in 2 is the source of their potential biological activity [5] that can be modified
by the presence of other pharmacophoric groups.
Results and Discussion
Scheme 1 shows the products obtained from the reaction between homophthalic anhydride (3) and
imine 4.
Scheme 1
O
HO
O
N
HO
O
N
H
N
O
O
O
different
4
3 +
+
+
+
conditions
O
O
COOH
O
O
O
trans-5
cis-5
6
7
Preliminary experiments were carried out to ensure high yields and stereoselectivity. The reaction
was performed using 1 mmol of each reactant under different conditions (Table 1). In general, the
expected products obtained were cis-5 and trans-5 along with by-products 6 and 7. The formation of
the by-products can be attributed to decomposition of 4 to the corresponding parent aldehyde and
amine in the course of the reaction [21,22]. The ratios between the acid products (containing 5 and 6)
and 7 were determined after work up of the reaction mixtures. Compound 7 is known, but was
previously prepared in a different manner [27]. The ratios between trans-5, cis-5 and 6 in the acid
1
products were determined by H-NMR spectroscopy from the integrals of relevant protons and are
shown in Table 1. The signals for the protons at C-3 (5.07 ppm for cis-5 and 5.29 ppm for trans-5) and

Molecules 2006, 11
405
at C-4 (4.64 ppm for cis-5 and 4.24 ppm for trans-5) were used for 5 [15,17]. In the case of product 6
the methylene protons (3.92 ppm) were taken into account. The configuration of each isomer of 5 was
determined on the basis of J 3,4. By analogy to Refs. [15] and [17], a trans configuration was attributed
to the isomer with the smaller J 3,4 (0 Hz) and a cis configuration to the one with the greater J 3,4 (5.75
Hz).
The data of Table 1 show that the reaction in aprotic solvents like dichloroethane and benzene
(items 1-3) leads always to a mixture of cis-5, trans-5 and by-products 6 and 7. Independently of the
great difference in temperature, the trans isomer of acid 5 is the preferred diastereoisomer. The use of
pyridine as a solvent and eventually as a basic catalyst in reactions of this type is now reported for the
o
first time. Both at 0 C and boiling pyridine (items 4 and 5), the trans isomer of 5 was obtained in
almost quantitative yields and the by-products 6 and 7 could not be isolated. Thus, these two
experiments show that the use of pyridine ensures complete stereoselectivity of the reaction and the
highest yield of the cyclic product with trans configuration.
Table 1. Ratios among Products of the Reaction of Homophthalic Anhydride (3) and Imine
4 under Different Conditions.a, b
Reaction conditions
Ratio (%)
No
Solvent
Temperature (oC)
Acidic residue/7c
cis-5/trans-5/6d
1
2
3
4
5
Dichloroethane
Dichloroethane
Benzene
Pyridine
Pyridine
83
0
80
116
0
83/17
88/12
84/16
100/ -
100/ -
19/41/40
15/32/53
20/45/35
traces/99/ -
traces/99/ -
a The reaction time was 15 min and complete consumption of 3 was confirmed by TLC.
b The yield was 100% in all cases after work up of the reaction mixture.
c Yields of the obtained acidic residue and 7 before recrystallisation.
d The ratio was determined by 1H NMR integrals of the obtained acidic residue (see text).
To obtain trans-5 in greater quantities for the subsequent transformations, the reaction was
performed on a large scale (6-140 mmols) in dichloroethane or pyridine. The results obtained were in
agreement with the data found for the small scale experiments.
Scheme 2 shows the synthetic route to the target 4-aminomethyl-1,2,3,4-tetrahydroisoquinolin-1-
ones (11). The direct esterification of acid trans-5 leads to methyl ester 8. The latter was reduced with
lithium borohydride in tetrahydrofuran to the corresponding hydroxymethyl derivative 9. The
reduction did not affect the amide group. Alcohol 9 was converted to the corresponding tosylate 10.
Reaction of 10 with the secondary cyclic amines, denoted as NuH, yielded tetrahydroisoquinolinones
11a-g. In all cases, the reaction mixture was refluxed until complete consumption of the tosylate as
observed by TLC. Ester 8 was reduced completely with lithium aluminium hydride to
tetrahydroisoquinoline alcohol 12.

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406
Scheme 2.
HO
O
N
MeO
O
N
HO
TosO
O
O
O
O
CH3OH, conc. H2SO4
LiBH4 / THF
TosCl / Pyridine
N
N
O
O
O
O
trans-5
8
9
10
LiAlH4 / THF,
NuH / Toluene,
Nu
HO
O
O
N
O
N
12
11a-g
Comp
NuH
NH
N
Comp
NuH
NH
N
F
11a
11e
NH
O
NH
11b
11c
11f
F
F
F
11g
NH
S
N
NH
NH
Cl
11d
N
1
1
The description of H-NMR spectra uses the arbitrary numbering given in formula 11d. The H-
NMR signals of 11d were assigned by COSY experiments and these data were taken into account in
the analysis of the other 1H-NMR spectra. On the basis of the value of J 3,4, all compounds 8-12 have
trans configuration. The starting compound for their synthesis is trans acid 5, i.e. all reactions
performed are stereospecific. This conclusion is expected since the reactions do not affect the
stereogenic centers but it is not trivial since it is known that epimerization can occur in some cases of
esterification or reduction.
15
Cl
N
15
14
11
N
14
5
13
10
12
O
4
6
3
2N
7
1
9
8
O
11d

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407
The target compounds 11a-g contain not only the fragment given in bold in formula 2 but also
other pharmacophores like furan and piperazine groups. Thus, different biological activity is expected
for them and their screening is being carried out.
Conclusions
The cycloaddition between homophthalic anhydride and an imine gave under different conditions
the expected diastereomeric tetrahydroisoquinolinone carboxylic acids along with two by-products.
The reaction proceeded in almost quantitative yields and stereoselectively in the presence of pyridine
at different temperatures furnishing the acid with trans configuration. A four-step transformation of the
carboxylic group of the trans acid resulted in stereospecific synthesis of seven
tetrahydroisoquinolinones containing different pharmacophoric groups.
Acknowledgements
Thanks are due to Johnson & Johnson, R & D, Janssen Pharmaceutica, Belgium, for financial
support of the project.
Experimental
General
Melting points were determined on a Kofler hot stage and are uncorrected. The IR spectra were
taken on a Specord 75 and are reported in cm-1. Nujol was used for cis-5, trans-5, 6 and 7 and
1
chloroform for all other compounds. The H-NMR spectra were obtained on a Bruker AM400
spectrometer at 400.13 MHz and Bruker Avance DRX-250 spectrometer at 250.1 MHz in
deuteriochloroform as solvent, if not stated otherwise. The chemical shifts are given in ppm (δ)
relative to tetramethylsilane used as internal standard. Elemental analyses were performed in the
analytical laboratory at the Faculty of Chemistry, University of Sofia. TLC was carried out on
precoated 0.2 mm Merck silica gel 60F254 plates. Merck silica gel 60 (0.040-0.063 mm) was used for
chromatographic filtration and flash chromatography.
(±)-trans- and (±)-cis-2-Benzyl-3-(furan-2-yl)-1-oxo-1,2,3,4-tetrahydro-4-isoquinoline Carboxylic
Acid (trans-5 and cis-5) and By-products 6 and 7: General Procedure for Determination of the Ratios
of the Products Obtained from 3 and 4 on a Small Scale Experiments
A solution of imine 4 (0.185 g, 1 mmol) in dry solvent (0.7 mL) was added dropwise over 5 min.
to a suspension of homophtalic anhydride (3, 0.162 g, 1 mmol) in dry solvent (1 mL). The reaction
mixture was stirred at the corresponding temperature (see Table 1) for 15 min. Тhe absence of 3 was
confirmed by TLC. The reaction mixture was diluted with dichloromethane (5 mL, entries 1 and 2 of
Table 1) or with toluene (5 mL, entry 3 of Table 1), when non-polar solvents were used. In the cases
when pyridine was used as a polar solvent (entries 4 and 5 of Table 1), the reaction mixture was
diluted with water (50 mL), extracted three times with dichloromethane and the organic layers were

Molecules 2006, 11
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washed once with aqueous HCl (1:1). For all cases, the organic layers obtained were washed three
times with 10 % sodium hydroxide. The amount of the product 7 was determined after evaporation of
the relevant organic solvents (entries 1 to 3 of Table 1). The alkaline solutions were acidified,
extracted three times with ethyl acetate, the combined organic layers were washed twice with water,
dried (sodium sulfate) and evaporated under reduced pressure leaving a brown oil containing the acid
1
products 5 and 6. The cis-5/trans-5/6 ratios were determined from the H-NMR integration (DMSO-
d6), as described above. The data obtained are summarised in Table 1. The characterisation of the
products is given below.
Reaction between 3 and 4 Performed on a Large Scale in Dichloroethane.
A solution of imine 4 (1.110 g, 6 mmol) in dry dichloroethane (5 mL) was added dropwise to a hot and
stirred suspension of homophtalic anhydride (3, 0.972 g, 6 mmol) in dry dichloroethane (5 mL). The
reaction mixture was boiled at 83 °C and stirred for 45 min. The absence of 3 was established by TLC.
The reaction mixture was left overnight. The yellow crystals of 7 were collected by filtration (0.124 g,
9 %). The filtrate was extracted three times with 10 % sodium hydroxide and the alkaline solutions
were acidified and then extracted three times with ethyl acetate. The organic layers were washed twice
with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure leaving
a dark brown oil (1.68 g). The acid products cis-5, trans-5 and 6 were separated by flash
chromatography (toluene-ethyl acetate 4.7:0.3) in yields of 9 %, 19 % and 10 %, respectively. A mixed
fraction containing both cis-5 and trans-5 was also obtained (7 %).
(±)-cis-2-Benzyl-3-(furan-2-yl)-1-oxo-1,2,3,4-tetrahydro-4-isoquinoline Carboxylic Acid (cis-5).
White crystals, mp 172-174 oC; Anal. Calc. For C21H17NO4: C, 72.61; H, 4.93. Found: C, 72.58; H,
1
5.15; H-NMR (DMSO-d6): 4.02 (d, 1H, -CH2C6H5, J = 15.5 Hz), 4.64 (d, 1H, 4-H, J = 5.5 Hz), 5.07
(d, 1H, 3-H, J=5.75 Hz), 5.26 (d, 1H, -CH2C6H5, J =15.5 Hz), 5.99-6.01 (m, 1H, 11-H), 6.25-6.27 (m,
1H, 10-H), 7.27-7.34 (m, 5H, phenyl protons), 7.42-7.48 (m, 2H, 5,12-H), 7.52-7.59 (m, 1H, 6-H),
7.64-7.67 (m, 1H, 7-H), 8.00-8.04 (m, 1H, 8-H); IR: 1730 (CO2H, dimer), 1630 (CO).
(±)-trans-2-Benzyl-3-(furan-2-yl)-1-oxo-1,2,3,4-tetrahydro-4-isoquinoline Carboxylic Acid (trans-5).
White crystals, mp 195-197 oC. Anal. Calc. For C21H17NO4: C, 72.61; H, 4.93. Found: C, 72.59; H,
1
4.92; H-NMR (DMSO-d6): 4.16 (d, 1H, -CH2C6H5, J = 15.04 Hz), 4.24 (s, 1H, 4-H), 5.18 (d, 1H, -
CH2C6H5, J = 15.0 Hz), 5.29 (s, 1H, 3-H), 5.94-6.00 (m, 1H, 11-H), 6.21-6.27 (m, 1H, 10-H), 7.22-
7.29 (m, 5H, phenyl protons), 7.34-7.36 (m, 1H, 5-H), 7.40-7.44 (m, 1H, 12-H), 7.48-7.54 (m, 2H, 6,7-
H), 7.87-7.94 (m, 1H, 8-H); IR: 1720 (CO2H, dimer), 1700 (CO2H, monomer), 1630 (CO).
2-[2-(Benzylamino)-2-oxoethyl]benzenecarboxylic Acid (6).
White crystals, mp 141-143 oC; Anal. Calc. For C16H15NO3: C, 71.36; H, 5.61. Found: C, 71.00; H,
5.77; 1H-NMR (DMSO-d6): 3.92 (s, 2H, -CH2CO-), 4.27 (d, 2H, -CH2C6H5, J = 5.9 Hz), 7.22-7.51 (m,

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8H, phenyl protons), 7.82-7.85 (m, 1H, phenyl proton), 8.38 (t, 1H, NH, J = 5.9 Hz); IR: 3300 (NH),
1710 and 1610 (CO).
4-(Furan-2-yl)methylidene-1H-isochromene-1,3-dione (7).
Yellow crystals, mp. 209-215 oC (lit. [27] mp 212 oC); Anal. Calc. For C14H8O4: C, 70.00; H, 3.36.
Found: C, 70.14; H, 3.16; 1H-NMR: 6.61-6.63 (m, 1H, furan), 7.28-7.43 (m, 2H, furan), 7.67-7.77 (m,
2H, phenyl protons), 7.85 (s, 1H, methyne proton), 8.13-8.16 (m, 2H, phenyl protons); IR: 3300 (NH),
1710 and 1610 (CO).
Reaction between 3 and 4 Performed on a Large Scale in Pyridine.
A solution of imine 4 (25.9 g, 0.14 mol) in dry pyridine (100 mL) was added dropwise over 30 min
to a solution of homophthalic anhydride (3, 22.68 g, 0.14 mol) in dry pyridine (150 mL). The reaction
mixture was boiled at 116 °C and stirred for 15 min., until the absence of 3 was established by TLC.
The reaction mixture was diluted with water (300 mL) and extracted three times with dichloromethane.
The organic layers were washed once with HCl (1:1) and three times with 10 % sodium hydroxide.
The alkaline solutions were acidified, extracted three times with ethyl acetate. The combined organic
layers were washed twice with water, dried (sodium sulfate) and evaporated affording crystals of
trans-5 (39.2 g, 80 %).
(±)-trans-Methyl-2-Benzyl-3-(furan-2-yl)-1-oxo-1,2,3,4-tetrahydro-4-isoquinoline Carboxylate (8).
Concentrated sulfuric acid (14.7 mL, 26.95 g, 0.28 mol) was added dropwise upon stirring to a hot
solution of trans-5 (39.20 g, 0.11 mol) in a mixture of methanol (148 mL, 140.80 g, 4.4 mol) and
toluene (200 mL). The reaction mixture was refluxed for 3.5 h. Then the reaction mixture was cooled,
diluted with toluene (200-250 mL) and washed three times with water and twice with 10 % sodium
carbonate. The organic layer was dried (sodium sulfate) and toluene was evaporated under reduced
pressure affording crystals of 8 in 76 % yield, mp 124-126 oC; Anal. Calc. For C22H19NO4: C, 73.12; H,
5.30. Found: C, 73.15; H, 5.12; 1H-NMR: 3.13 (s, 3H, -COCH3), 3.69 (d, 1H, -CH2C6H5, J = 14.6 Hz),
3.88 (s, 1H, 4-H), 5.04 (s, 1H, 3-H), 5.42 (m, 1H, -CH2C6H5), 5.63-5.69 (m, 1H, 11-H), 5.90-5.95 (m,
1H, 10-H), 6.93-6.95 (m, 1H, 5-H), 7.04-7.11 (m, 6H, 12-H, phenyl protons), 7.22-7.23 (m, 2H, 6,7-H),
7.96-7.98 (m, 1H, 8-H); IR: 1740 and 1650 (CO).
(±)-trans-2-Benzyl-3-(furan-2-yl)-4-hydroxymethyl-1,2,3,4-tetrahydroisoquinolin-1-one (9).
To a stirred suspension of potassium borohydride (10.8 g, 0.2 mol) and lithium chloride (8.5 g, 0.2
mol) in dry tetrahydrofuran (100 mL), solution of ester 8 (29.7 g, 0.08 mol) in dry tetrahydrofuran (70
mL) was added dropwise. The reaction mixture was stirred at room temperature for 15 hours,
concentrated under reduced pressure, poured into water and extracted with ethyl acetate. The organic
layer was washed with water, dried (sodium sulfate) and evaporated to yield compound 9 as an oil.
o
The latter was crystallized from ethyl acetate giving white crystals, (23.9 g, 90%), mp 105-106 C.
1
Anal. Calc. For C21H19NO3: C, 75.66; H, 5.74; N, 4.20. Found: C, 75.30; H, 5.43; N, 4.54; H-NMR:

Molecules 2006, 11
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3.20-3.34 (m, 2H, -CH2OH), 3.43-3.52 (m, 1H, -OH), 3.81 (d, 1H, -CH2C6H5, J = 14.3 Hz), 4.85 (s,
1H, 4-H), 5.85 (d, 1H, -CH2C6H5, J = 14.3 Hz), 5.90 (s, 1H, 3-H), 5.91-5.95 (m, 1H, 11-H), 6.16-6.19
(m, 1H, 10-H), 7.09-7.16 (m, 1H, 5-H), 7.25-7.28 (m, 1H, 12-H), 7.28-7.46 (m, 7H, 6,7-H, phenyl
protons), 8.13-8.17 (m, 1H, 8-H); IR: 3610 (OH), 1640 (CO).
(±)-trans-2-Benzyl-1-oxo-3-(furan-2-yl)-4-tosyloxymethyl-1,2,3,4-tetrahydroisoquinolin-1-one (10).
p-Toluenesulfonyl chloride (30.5 g, 0.16 mol) was added in portions to a solution of 9 (26.4 g, 0.08
mol) in pyridine (150 mL) maintained at -5 oC. The reaction mixture was stirred at room temperature
for 15 hours, poured into water and extracted with ethyl acetate. The organic layer was thoroughly
washed with water, dried (sodium sulfate) and evaporated to dryness. Compound 10 was obtained as a
red oil, (36.6 g, 94%). Tosylate 10 was used in the next stage of the reaction scheme without any
preliminary purification. The NMR-spectra of compound 10 is similar to that of the starting alcohol 9
and shows a singlet for the methyl group of the p-toluenesulfonyl group, signals for four additional
aromatic protons and the signal for the hydroxylic proton was absent.
General Procedure for the Preparation of (±)-trans-2-Benzyl-1-oxo-3-(furan-2-yl)-4-(N,N-disubstitu-
tedaminomethyl)-1,2,3,4-tetrahydroisoquinolin-1-ones (11a-g).
The secondary amine NuH (Scheme 2, 18 mmol) was added to a solution of tosylate 10 (3.0 g, 6
mmol) in toluene (15 mL). The reaction mixture was refluxed (20-49 hrs) until 10 was no longer
present, as indicated by TLC. Ethyl acetate was added after cooling. The organic layer was thoroughly
washed with water and dried (sodium sulfate). The solvents were removed under reduced pressure and
the resulting brown oil was purified by chromatographic filtration (4.8:0.2 dichloromethane-ethyl
acetate) and/or flash chromatography (4.5:0.5 hexane-ethyl acetate) and subsequent recrystallisation
(from 4:1 hexane-ethyl acetate).
(±)-trans-2-Benzyl-1-oxo-3-(furan-2-yl)-4-[(piperidin-1-yl)methyl)]-1,2,3,4-tetrahydroisoquinolin-1-
one (11a).
This compound was obtained from 10 and piperidine as white crystals (0.580 g, 24 %) after flash
o
chromatography and recrystallisation mp 124-126 C; Anal. Calc. For C26H28N2O2: C, 77.97; H, 7.05.
1
Found: C, 77.91; H, 7.28; H-NMR: 1.54-1.63 (m, 6H, 15-H),1.96-2.00 (m, 2H, 14-H), 2.48-2.54 (m,
1H, 4-H), 2.59-2.61 (m, 2H, 14-H), 3.49 (dd, 1H, 13-H,J = 15.5, 8 Hz), 4.05 (d, 1H, 9-H, J = 14.3 Hz),
5.46 (s, 1H, 3-H), 5.99 (d, 1H, 9-H, J = 14.3 Hz), 6.18-6.19 (m, 1H, 11-H), 6.45-6.46 (m, 1H, 10-H),
7.26-7-33 (m, 1H, 5-H), 7.48-7.79 (m, 8H, 6,7,12-H, phenyl protons), 8.41-8.49 (m, 1H, 8-H); IR:
1660 (CO).
(±)-trans-2-Benzyl-1-oxo-3-(furan-2-yl)-4-[(4-phenyl-piperazin-1-yl)methyl)]-1,2,3,4-tetrahydroiso-
quinolin-1-one (11b).
This compound was obtained from 10 and N-phenylpiperazine as white crystals (1.1 g, 38 %) after
o
chromatographic filtration, flash chromatography and recrystallisation; mp 189 C; Anal. Calc. For

Molecules 2006, 11
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1
C31H31N3O2: C, 77.96; H, 6.54; N, 8.80. Found: C, 78.22; H, 6.68; N, 8.55; H-NMR: 1.83-1.88 (m,
2H, 14-H), 2.09 (dd, 1H, 13-H,J = 16.0, 8 Hz), 2.28-2.34 (m, 1H, 4-H), 2.50-2.55 (m, 2H, 14-H),2.91-
3.09 (m, 4H, 15-H), 3.22 (dd, 1H, 13-H, J = 16.0, 8 Hz), 3.69 (d, 1H, 9-H, J = 14.3 Hz), 5.16 (s, 1H, 3-
H), 5.77 (d, 1H, 9-H, J = 14.3 Hz), 5.90-5.91 (m, 1H, 11-H), 6.16-6.17 (m, 1H, 10-H), 6.80-6.85 (m,
3H, 5,6,7-H), 7.03-7.05 (m, 1H, 12-H), 7.20-7.48 (m, 10H, phenyl protons), 8.13-8.15 (m, 1H, 8-H);
IR: 1660 (CO).
(±)-trans-2-Benzyl-1-oxo-3-(furan-2-yl)-4-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl)methyl)]-1,2,-
3,4-tetrahydroisoquinolin-1-one (11c).
This compound was obtained from 10 and 3-(trifluoromethyl)-N-phenylpiperazine as white
crystals (1.3 g, 40 %) after chromatographic filtration, flash chromatography and recrystallisation; mp
170-172.5 oC; Anal. Calc. For For C32H30N3O2F3: C, 70.43; H, 5.55; N, 7.70. Found: C, 70.50; H, 5.40;
N, 7.38; 1H-NMR: 1.66-1.71 (m, 2H, 14-H), 1.93 (dd, 1H, 13-H,J = 17.0, 7.4 Hz), 2.11-2.17 (m, 1H, 4-
H), 2.35-2.38 (m, 2H, 14-H),2.75-2.83 (m, 4H, 15-H), 3.05 (dd, 1H, 13-H, J = 15.4, 8.2 Hz), 3.51 (d,
1H, 9-H, J = 14.3 Hz), 4.97 (s, 1H, 3-H), 5.61 (d, 1H, 9-H, J = 14.3 Hz), 5.73-5.74 (m, 1H, 11-H),
5.99-6.00 (m, 1H, 10-H), 6.79-6.81 (m, 1H, 5-H), 6.85-6.88 (m, 3H, 6,7,12-H), 7.07-7.31 (m, 9H,
phenyl protons), 7.96-7.98 (m, 1H, 8-H); IR: 1660 (CO).
(±)-trans-2-Benzyl-1-oxo-3-(furan-2-yl)-4-[4-(3-chlorophenyl)-piperazin-1-yl)methyl)]-1,2,3,4-tetra-
hydroisoquinolin-1-one (11d).
This compound was obtained from 10 and 1-(3-chlorophenyl)-piperazine as white crystals (0.82 g,
o
23 %) after chromatographic filtration, flash chromatography and recrystallisation; mp 187-189 C;
1
Anal. Calc. For C31H30ClN3O2: C, 72.72; H, 5.91. Found: C, 72.49; H, 5.78; H-NMR: 1.62-1.67 (m,
2H, 14-H), 1.90 (dd, 1H, 13-H, J = 16.7, 8.8 Hz), 2.09-2.15 (m, 1H, 4-H), 2.31-2.34 (m, 2H, 14-H),
2.75-2.83 (m, 4H, 15-H), 3.03 (dd, 1H, 13-H, J = 15.6, 8.3 Hz), 3.50 (d, 1H, 9-H, J = 14.3 Hz), 4.96 (s,
1H, 3-H), 5.60 (d, 1H, 9-H, J = 14.3 Hz), 5.72-5.73 (m, 1H, 11-H), 5.97-5.99 (m, 1H, 10-H), 6.52-6.93
(m, 4H, 5,6,7,12-H), 7.03-7.29 (m, 9H, phenyl protons), 7.94-8.04 (m, 1H, 8-H); IR: 1660 (CO).
(±)-trans-2-Benzyl-1-oxo-3-(furan-2-yl)-4-[4-fluorophenylpiperazin-1-yl)methyl)]-1,2,3,4-tetrahydro-
isoquinolin-1-one (11e).
This compound was obtained from 10 and 1-(4-fluorophenyl)piperazine as white crystals (1.2 g, 40
%) after chromatographic filtration, flash chromatography and recrystallisation; mp 150-152 oC; Anal.
Calc. For C31H30FN3O2: C, 75.13; H, 6.10. Found: C, 74.85; H, 5.67; 1H-NMR: 1.89-1.94 (m, 2H, 14-
H), 1.87 (dd, 1H, 13-H, J = 16.7, 8.9 Hz), 2.34-2.40 (m, 1H, 4-H), 2.58-2.61 (m, 2H, 14-H), 2.86-2.95
(m, 4H, 15-H), 3.28 (dd, 1H, 13-H, J = 16.8, 8.9 Hz), 3.75 (d, 1H, 9-H, J = 14.3 Hz), 5.21 (s, 1H, 3-H),
5.83 (d, 1H, 9-H, J = 14.3 Hz), 5.96-5.97 (m, 1H, 11-H), 6.22-6.23 (m, 1H, 10-H), 6.83-7.00 (m, 3H,
5,6,7-H), 7.09-7.11 (m, 1H, 12-H), 7.28-7.47 (m, 9H, phenyl protons), 8.19-8.21 (m, 1H, 8-H); IR:
1660 (CO).

Molecules 2006, 11
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(±)-trans-2-Benzyl-1-oxo-3-(furan-2-yl)-4-[4-(morpholin-4-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-
1-one (11f).
This compound was obtained from 10 and morpholine as white crystals (0.89 g, 37 %) after
o
chromatographic filtration, flash chromatography and recrystallisation; mp 135-137 C; Anal. Calc.
For C25H26N2O3: C, 74.60; H, 6.51. Found: C, 74.82; H, 6.62; 1H-NMR: 1.38-1.49 (m, 2H, 14-H), 1.87
(dd, 1H, 13-H, J = 16.7, 8.7 Hz), 1.98-2.07 (m, 1H, 4-H), 2.11-2.16 (m, 2H, 14-H), 3.00 (dd, 1H, 13-H,
J = 15, 8.6 Hz), 3.24-3.28 (m, 4H, 15-H) 3.50 (d, 1H, 9-H, J = 14.3 Hz), 4.96 (s, 1H, 3-H), 5.60 (d, 1H,
9-H, J = 14.3 Hz), 5.71-5.72 (m, 1H, 11-H), 5.97-5.98 (m, 1H, 10-H), 6.77-6.84 (m, 1H, H-5), 6.93-
7.41 (m, 8H, 6,7,12-H, phenyl protons), 7.93-7.96 (m, 1H, 8-H); IR: 1660 (CO).
(±)-trans-2-Benzyl-1-oxo-3-(furan-2-yl)-4-[4-(thiomorpholin-4-yl)methyl]-1,2,3,4-tetrahydroisoquino-
lin-1-one (11g).
This compound was obtained from 10 and thiomorpholine as white crystals (1.26 g, 50 %) after
o
chromatographic filtration, flash chromatography and recrystallisation; mp 162-164 C; Anal. Calc.
For C25H26N2O2S: C, 71.73; H, 6.26; N, 6.69. Found: C, 71.90; H, 6.17; N, 6.68; 1H-NMR: 1.73 -1.78
(m, 2H, 14-H), 2.17-2.20(m, 4H, 13-, 15-H), 2.39-2.44 (m, 2H, 15-H), 2.96-2.98 (m, 1H, 4-H), 2.11-
2.16 (m, 2H, 14-H), 3.48 (d, 1H, 9-H, J = 14.3 Hz), 4.87 (s, 1H, 3-H), 5.59 (d, 1H, 9-H, J = 14.3 Hz),
5.71-5.72 (m, 1H, 11-H), 5.97-5.98 (m, 1H, 10-H), 6.82-6.83 (m, 1H, H-5), 7.04-7.30 (m, 8H, 6,7,12,-
H, phenyl protons), 7.93-7.96 (m, 1H, 8-H); IR: 1660 (CO).
(±)-trans-2-Benzyl-3-(furan-2-yl)-4-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (12).
The completely reduced alcohol 12 was prepared from 8 (0.824 g, 2.3 mmol) following literature
procedures [21, 22] with a reaction time of 2 hours. It was obtained as colorless crystals (from ethyl
o
acetate), (0.520 g, 71 %); mp 103-105 C; Anal. Calc. For C21H21NO2: C, 78.97; H, 6.63. Found: C,
78.99; H, 6.71; 1H-NMR: 3.31 (br s, 1H, -OH), 3.55 (d, 1H, -CH2C6H5, J = 15.5 Hz), 3.86 (d, 1H, 13-
H, J = 13 Hz), 4.01 (d, 1H, -CH2C6H5, J = 15.5 Hz), 4.14 (d, 1H, 13-H, J = 13 Hz), 4.15 (d, 1H, 1-H, J
= 10 Hz), 4.30 (d, 1H, 1-H, J = 10 Hz), 4.34-4.36 (m, 1H, 4-H), 4.61 (s, 1H, 3-H), 5.94-5.95 (m, 1H,
11-H), 6.43-6.44 (m, 1H, 10-H), 7.17-7.20 (m, 1H, 5-H), 7.31-7.40 (m, 1H, 12-H), 7.44-7.61 (m, 7H,
6,7-H, phenyl protons), 7.63-7.67 (m, 1H, 8-H); IR: 3640 (OH).
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Sample Availability: Compounds cis-5, trans-5,6-9, trans-11a-e, and trans-11g are available in 20 mg
amounts from the authors.
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