New trans/cis tetrahydroisoquinolines. 1. trans-2-Benzyl-3-(1-methyl-1h-pyrrol-2-yl)-4-substituted-1,2,3,4- tetrahydroisoquinolin-1-ones and corresponding tetrahydroisoquinolines

Article abstract of DOI:10.1002/jhet.5570390134

The reaction of homophthalic anhydride and N-(1-methyl-1H-pyrrol-2-yl-methylidene)-benzylamine in boiling benzene afforded as a main product the expected substituted trans-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid 5. The carboxylic group of 5 was transformed in four steps into cyclic amino-methyl groups yielding numerous new tetrahydroisoquinolinones 11a-j incorporating a given fragment of pharmacological interest. Reduction of 11a-j was studied.

Full text of DOI:10.1002/jhet.5570390134

Jan-Feb 2002
New trans/cis Tetrahydroisoquinolines. 1. trans-2-Benzyl-3-(1-methyl-
1H-pyrrol-2-yl)-4-substituted-1,2,3,4-tetrahydroisoquinolin-1-ones and
Corresponding Tetrahydroisoquinolines
229
1
*
I. D. Kozekov , R. I. Koleva and M. D. Palamareva
University of Sofia, Faculty of Chemistry, 1 James Bouchier Avenue
Sofia 1164, Bulgaria
Received June 26, 2001
The reaction of homophthalic anhydride and N-(1-methyl-1H-pyrrol-2-yl-methylidene)-benzylamine in
boiling benzene afforded as a main product the expected substituted trans-1,2,3,4-tetrahydroisoquinoline-4-
carboxylic acid 5. The carboxylic group of 5 was transformed in four steps into cyclic amino-methyl groups
yielding numerous new tetrahydroisoquinolinones 11a-j incorporating a given fragment of pharmacological
interest. Reduction of 11a-j was studied.
J. Heterocyclic Chem., 39, 229 (2002).
Substituted 1,2,3,4-tetrahydroisoquinolines with asym-
3
4
metric C and C exist in two racemic diastereoisomeric
forms, namely (±)-trans and (±)-cis that will be denoted
simply by trans and cis. These compounds are important
from synthetic and applied point of view. Their structure is
incorporated in various alkaloids [1,2] and pharmacologi-
cally important compounds (see for instance refs. 3 and 4).
The synthesis of trans and/or cis isomers of such tetrahy-
droisoquinolines is possible by classical reactions [5,6] but
the starting compounds are difficult to obtain. The com-
pounds of type 1 can be prepared by the one step reaction
between homophthalic anhydride and an imine, the reac-
tion being reported almost simultaneously from two inde-
pendent laboratories [7,8]. Since 1977, this reaction has
been widely applied [9-21] for preparation of substituted
tetrahydroisoquinolinones and polycyclic heterocycles
when acyclic and cyclic imines are used, respectively.
Bigg and co-workers [22] use the same reaction in combi-
nation with other well known reactions to obtain various
compounds 2 with a primary amino-methyl group. The
authors claim that the fragment given in bold is the reason
some of the compounds show sub-micromolar affinity to
the NMDA receptor. Another type of cyclization has been
used [23] for enantioselective synthesis of tetrahydroiso-
quinolinones.
are available in the products functional groups. Attention is
paid to the stereochemical course of the reactions.
The reaction between homophtalic anhydride 3 and the
imine 4 was carried out in boiling benzene. This enabled us
to obtain as a main product, in 70% yield, only the trans iso-
mer of tetrahydroisoquinolinone carboxylic acid 5. The con-
3,4
figuration was assigned on the basis of the small [7,8] J
of
1.6 Hz. Thus contrary to ref. 22, we succeeded in perform-
ing a diastereoselective reaction, thus avoiding the necessity
of isomerisation of a mixture of cis and trans acids. The
acyclic compounds 6a and 7a were isolated as by-products.
In some cases [15,24], Perkin condensation between
homophtalic anhydrides and the aldehyde used for the
preparation of the imine takes place as a side reaction. The
formation of the corresponding products indicates that the
imines can decompose to the parent aldehyde and amine in
the course of the reaction with 3. Compound 6a probably
results from the opening of the anhydride ring of 3 by nucle-
The aim of this and future related papers is to further spec-
ify the scope and limitation of the reaction of homophthalic
anhydrides and imines and subsequent transformations that
3
ophilic attack of benzyl amine on the C carbonyl group.
Perkin type condensation of compound 6a with the
Scheme 1

230
I. D. Kozekov, R. I. Koleva and M. D. Palamareva
Vol. 39
Scheme 3
corresponding aldehyde would lead to Z or E 7a.
Compounds 6a and 7a and the corresponding methyl esters
1
6b and 7b were characterised by H and COSY spectra.
1
Compound 6b was proved by mp and H to be identical
with the relevant compound described in ref. 16. Its struc-
ture was further proved by HMBC spectra. Detailed analysis
of these spectra revealed that the protons of the two methyl-
ene groups at 3.93 and 4.40 ppm are coupled with same car-
bonyl carbon at 171.2 ppm, while the methyl protons at 3.88
ppm are coupled with the other carbonyl carbon at 169.0
ppm. This analysis supports the structures of 6a and 6b.
Cushman and Madaj [11] consider the reaction between
homophtalic anhydride and an imine as a non-concerted
addition of the imine to positions 1 and 4 of the anhydride,
1
the formation of C - N bond preceding the formation of
3
4
C – C bond. These authors base this conclusion on the
application of the Hammett equation using three different
solvents. The values found (0.206 and 0.088) of the reac-
tion constant, ρ, are close to zero when the solvent is
methanol or formamide. Taking into account the use of ρ
for mechanism elucidation [25,26], we assume that the
synchronous mechanism of the reaction between a
homophthalic anhydride and an imine, as shown in
Scheme 2, should not be excluded since such a mechanism
requires ρ ca. 0. It is worth noting that the reaction of
homophthalic anhydrides with dienophiles is regarded [27]
as [4+2] cycloaddition, i.e. as a pericyclic reaction show-
ing ρ ca. 0 in general.
Scheme 2
Scheme 3 gives the route of acid 5 to the final com-
pounds 11 and 12. The pathway to 11a-j is similar to that
used by Bigg and co-workers [22] to prepare a given
tetrahydroisoquinolinone having a cyclic amino-methyl
group at position 4.
The conversion of acid 5 in methyl ester 8 was accom-
plished by treatment with iodomethane in the presence of
potassium carbonate since the direct esterification of acid
5 lead to a mixture of unidentified products. Ester 8 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 any of
the secondary amines, denoted as NuH, yielded, after a
prolonged heating, tetrahydroisoquinolinones 11a-j.
Reduction of the latter with lithium aluminium hydride
gave tetrahydroisoquinolines 12a-j that could be also of
pharmacological interest.

Jan-Feb 2002
231
New trans/cis Tetrahydroisoquinolines
To a hot and stirred solution of homophthalic anhydride (23.89
g, 0.147 mole) in 220 mL dry benzene, N-(1-methyl-1H-pyrrol-2-
yl-methylidene)-benzylamine (4) (29.20 g, 0.147 mole) in 30 mL
dry benzene was added dropwise for 30 min. The reaction mix-
ture was refluxed for 15 min and left overnight. The colorless
crystals were filtered and washed with ethyl acetate yielding 33.9
g (64 %) of 5. The filtrate was extracted twice with 10 % sodium
hydroxide and the alkaline solutions were acidified, extracted
three times with ethyl acetate. The combined organic layers were
dried (sodium sulfate) and evaporated under reduced pressure
leaving a dark oil (14.2 g). Fractional recrystallisation of the lat-
ter from ethyl acetate gave an additional quantity of acid 5 (3.2 g,
6 %) along with 1.9 g (5 %) 6a and 3.4 g (6 %) 7a.
Ester 8 was reduced completely with lithium alu-
minium hydride to alcohol 13 that was converted to tosy-
late 14. Reaction of 14 with three secondary amines gave
12d,e,h in low yields because of the presence of great
number of side products. Thus, this shorter path from 8 to
12 is not convenient.
Starting from trans acid 5, compounds 8-12 obtained have
trans configuration, i.e. all reactions are stereospecific.
1
The description of the H nmr spectra uses the arbitrary
1
numbering given in formula 11d. The signals in H of 11e
and 12g were attributed by COSY experiments and these
data were taken into account in the analysis of the other
1
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-1-oxo-1,2,3,4-
tetrahydro-4-isoquinoline Carboxylic Acid (5).
H spectra.
Compound 5 was obtained as white crystals, mp 226-228°; ir
(Nujol): 1710 (CO H, dimer), 1700 (CO H, monomer), 1640
2
2
-1
1
(CON) cm ; H nmr (dimethyl sulfoxide-d ): δ 3.55 (s, 3H,
6
13-H), 3.86 (d, 1H, 9-H, J = 15.1 Hz), 4.13 (d, 1H, 4-H, J = 1.6
Hz), 5.20 (d, 1H, 9-H, J = 15.1 Hz), 5.27 (d, 1H, 3-H, J = 1.6 Hz),
5.31-5.33 (m, 1H, 10-H), 5.72-5.75 (m, 1H, 11-H), 6.63-6.65 (m,
1H, 12-H), 7.21-7.48 (m, 8H, phenyl protons), 7.96-8.00 (m, 1H,
9
8-H), 13.01 (br. s, 1H, CO H).
2
Anal. Calcd. for C H N O : C, 73.33; H, 5.59. Found: C,
22 20
2 3
73.66; H, 5.66.
2-[2-(Benzylamino)-2-oxoethyl]benzenecarboxylic Acid (6a).
This by-product was obtained as white crystals, mp 141-143°;
-1
The ir spectra of 11a-j show CO (amide) of 1640 cm .
The ir spectra of compounds 12a-j do not show a band for
a carbonyl group.
-1
1
ir (Nujol): NH 3300, CO 1710, 1610, cm ; H nmr (dimethyl
sulfoxide-d ): δ 3.92 (s, 2H, -CH CO-), 4.27 (d, 2H, -CH C H ,
6
2
2 6 5
Majority of the compounds prepared has passed pharma-
cological screening showing moderate activities [28].
J = 5.9 Hz), 7.22-7.51 (m, 8H, phenyl protons), 7.82-7.85 (m, 1H,
phenyl proton), 8.38 (t, 1H, NH, J = 5.9 Hz), 12.92 (s, 1H, -
CO H).
2
Anal. Calcd. for C H NO : C, 71.38; H, 5.62. Found: C,
71.38; H, 5.82.
16 15
3
EXPERIMENTAL
2-[1-[(Benzylamino)carbonyl]-2-(1-methyl-1H-pyrrol-2-
yl)ethenyl]benzenecarboxylic Acid (7a).
Melting points were determined on a Kofler hot stage and are
uncorrected. The ir spectra were acquired on a Specord 75 and
are reported in reciprocal centimeters. Nujol was used for 5, 6a
This by-product was obtained as white crystals, mp 194-195°;
1
-1
1
and 7a and chloroform for all other compounds. The H nmr
ir (Nujol): NH 3370, CO 1710, 1640 cm ; H nmr: δ 3.67 (s, 3H,
-CH ), 4.27 (dd, 1H, -CH C H , J = 15.4, 5.7 Hz), 4.40 (dd, 1H,
spectra were obtained on a Bruker AM400 NMR spectrometer at
400.13 MHz in deuteriochloroform as solvent, if not stated other-
wise. The chemical shift is given in ppm (δ) relative to tetram-
3
2 6 5
-CH C H , J = 15.4, 6.4 Hz), 5.05-5.07 (m, 1H, pyrrol), 5.80-
2
6 5
5.82 (m, 1H, pyrrol), 6.90-6.92 (m, 1H, pyrrol), 7.06-7.25 (m,
6H, phenyl protons), 7.44-7.50 (m, 2H, phenyl protons), 7.53 (s,
1H, =CH-), 7.70-7.74 (m, 1H, phenyl proton), 8.52 (t, 1H, -NH,
13
ethylsilane as internal standard. The C nmr spectrum of 6b was
obtained on the same spectrometer at 100.6 MHz in deuteriochlo-
roform. Mass spectra were recorded on a Hewlet Packard MS
5973 spectrometer and Hewlet Packard GC-MS 5372 using elec-
tron impact of 30 eV and 100 eV, respectively. The mass spectra
of 7b, 11d-g and 12c-g were acquired at 30 eV and those of the
remaining compounds at 100 eV. Elemental analyses were
obtained in the relevant laboratories at the Faculty of Chemisty,
University of Sofia and at the Institute of Organic Chemistry,
Bulgarian Academy of Sciences. Tlc was done on precoated 0.2
J = 5.9 Hz), 12.07 (s, 1H, -CO H).
2
Anal. Calcd. for C H N O : C, 73.31; H, 5.59. Found: C,
22 20
2 3
73.64; H, 5.93.
Methyl 2-[2-(Benzylamino)-2-oxoethyl]benzenecarboxylate
(6b).
This compound was obtained from the reaction of acid 6a and
diazomethane in diethyl ether at room temperature for 1 hour. It
was obtained as white crystals (ethyl acetate) in 90 %, mp 115-
mm Merck silica gel 60F plates. Mobile phases used are given
254
-
118° (lit., [16] 115-118°); ir: NH 3470, 3410, CO 1720, 1675 cm
in ref. 29. Merck silica gel 60 (0.040-0.063 mm) was used for
chromatographic filtration and flash-chromatography.
1
1
; H nmr: δ 3.88 (s, 3H, -CH ), 3.93 (s, 2H, -CH CO-), 4.40 (d,
3
2
2H, -CH NH, J = 5.8 Hz), 6.74 (broad s, 1H, -NH), 7.21-7.56 (m,
2
13
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-1-oxo-1,2,3,4-
tetrahydro-4-isoquinoline Carboxylic Acid (5) and by-products
6a and 7a.
8H, phenyl protons), 7.95-8.00 (m, 1H, phenyl proton); C nmr:
δ 42.9, 44.0, 53.0, 127.8 (2C), 128.0 (2C), 129.2 (2C), 130.2,
131.6, 133.0, 133.3, 137.9, 139.7, 169.0, 171.2.

232
I. D. Kozekov, R. I. Koleva and M. D. Palamareva
Vol. 39
Methyl 2-[1-[(Benzylamino)carbonyl]-2-(1-methyl-1H-pyrrol-2-
yl)ethenyl]benzenecarboxylate (7b).
acetate. The organic layer was thoroughly washed with water,
dried (sodium sulfate) and evaporated to dryness. The resulting
oil gave 10 as colorless crystals (chloroform) in 66%, mp 103-
105 °; ir: CO 1660 cm ; H nmr: 2.45 (s, 3H, 15-H), 3.30 (m,
1H, 4-H), 3.48 (s, 1H, 13-H), 3.76 (d, 1H, 9-H, J = 14.5 Hz), 3.82
(t, 1H, 14-H, J = 10.4 Hz), 3.97 (dd, 1H, 14-H, J = 10.4, 5.0 Hz),
4.86 (s, 1H, 3-H), 5.56-5.59 (m, 1H, 10-H), 5.57 (d, 1H, 9-H, J =
14.5 Hz), 5.86-5.89 (m, 1H, 11-H), 6.50-6.51 (m, 1H, 12-H),
7.03-7.06 (m, 1H, phenyl proton), 7.22-7.57 (m, 11H, phenyl
protons), 8.17-8.23 (m, 1H, 8-H).
This compound was obtained from 7a as described for 6b as
white crystals (ethyl acetate) in 80%, mp 140-142°; ir: NH 3470,
-1
1
-1
1
CO 1735, 1670, C=C 1620 cm ; H nmr: δ 3.76 (s, 6H, -CH ),
3
4.37 (dd, 1H, -CH C H , J = 15.2, 5.6 Hz), 4.61 (dd, 1H,
2
6 5
-CH C H , J = 15.2, 6.4 Hz), 4.94-4.95 (m, 1H, pyrrol), 5.64
2
6 5
(broad s, 1H, -NH), 5.85 (m, 1H, pyrrol), 6.66 (m, 1H, pyrrol),
7.21-7.40 (m, 6H, phenyl protons), 7.55-7.70 (m, 2H, phenyl pro-
tons), 7.79 (s, 1H, =CH-), 8.13-8.15 (m, 1H, phenyl proton); ms:
m/z 374 (molecular ion).
Anal. Calcd. for C H N O S: C, 69.59; H, 5.64. Found: C,
29 28
2 4
69.46; H, 5.70.
Anal. Calcd. for C H N O : C, 73.78; H, 5.92. Found: C,
22 22
2 3
73.60; H, 6.04.
General Procedure for the Preparation of (±)-trans-2-Benzyl-3-
(1-methyl-1H-pyrrol-2-yl)-4-(N,N-disubstituted-aminomethyl)-
1,2,3,4-tetrahydroisoquinolin-1-ones (11).
(±)-trans-Methyl-2-benzyl-3-(1-methyl-1H-pyrrol-2-yl)-1-oxo-
1,2,3,4-tetrahydro-4-isoquinoline carboxylate (8).
A relavent secondary amine NuH (21-28 mmoles) was added
to a solution of tosylate 10 (3.5 g, 7 mmoles) in 15 mL toluene.
The reaction mixture was refluxed (9-36 hrs) until 10 was con-
sumed, which was followed by tlc. Ethyl acetate (200 mL) was
added after cooling. The organic layer was thoroughly washed
with water and dried (sodium sulfate). The solvents were
removed under reduced pressure. The resulting brown oil was
purified by chromatographic filtration or flash chromatography.
To a mixture of potassium carbonate (9.77 g, 0.071 mole) and
acid 5 (25.5 g, 0.071 mole) in dimethylformamide (300 mL),
iodomethane (20.07 g, 0.142 mole) was added dropwise for 1
hour. The reaction mixture was stirred for 12 hours, added to
water and extracted with ethyl acetate. The organic layer was
washed with water, dried (sodium sulfate) and evaporated giving
an oil. The latter afforded 8 as white crystals (ethyl acetate) in
-1
1
80%, mp 145-146°; ir: CO 1740, 1640 cm ; H nmr: δ 3.42 (s,
3H, CO CH ), 3.48 (s, 3H, 13-H), 3.72 (d, 1H, 9-H, J = 14.8 Hz),
2
3
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(piperidin-1-
yl)methyl]-1,2,3,4-tetrahydroisoquinolin-1-one (11a).
3.83 (d, 1H, 4-H, J = 2.2 Hz), 5.08 (d, 1H, 3-H, J = 2.2 Hz), 5.65-
5.67 (m, 1H, 10-H), 5.66 (d, 1H, 9-H, J = 14.8 Hz), 5.91-5.92 (m,
1H, 11-H), 6.51-6.52 (m, 1H, 12-H), 7.05-7.07 (m, 1H, phenyl
proton), 7.21-7.34 (m, 5H, phenyl protons), 7.43-7.48 (m, 2H,
phenyl protons), 8.21-8.28 (m, 1H, 8-H); ms: m/z 374 (molecular
ion).
This compound was obtained as white crystals (ethyl acetate)
1
in 57%, mp 149-151°; H nmr: δ 1.32 (s, 6H, 16-H), 1.64-1.68
(m, 2H, 15-H), 2.02 (dd, 1H, 14-H, J = 12.0, 3.2 Hz), 2.23 (t,
1H, 14-H, J = 12.0 Hz), 2.27-2.46 (m, 2H, 15-H), 2.91 (dd, 1H,
4-H, J = 12.0, 3.0 Hz), 3.53 (d, 1H, 9-H, J = 14.0 Hz), 3.59 (s,
3H, 13-H), 5.18 (s, 1H, 3-H), 5.64-5.65 (m, 1H, 10-H), 5.77 (d,
1H, 9-H, J = 14.0 Hz), 5.91-5.92 (m, 1H, 11-H), 6.52-6.53 (m,
1H, 12-H,), 6.95-6.97 (m, 1H, phenyl proton), 7.26-7.39 (m,
7H, phenyl protons), 8.19-8.23 (m, 1H, 8-H); ms: m/z 413
(molecular ion).
Anal. Calcd. for C H N O : C, 73.78; H, 5.92. Found: C,
23 22
2 3
73.80; H, 6.13.
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-hydroxy-
methyl-1,2,3,4-tetrahydroisoquinolin-1-one (9).
To a stirred suspension of potassim borohydride (7.53 g, 0.140
mole) and lithium chloride (5.91 g, 0.140 mole) in tetrahydrofu-
ran (200 mL), ester 8 (20.86 g, 0.056 mole) dissolved in tetrahy-
drofuran (200 mL) was added dropwise. The reaction mixture
was stirred at room temperature for 13 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 affording crystals. The latter gave 9 as
white prisms (ethyl acetate) in 97%, mp 157-158°; ir: OH 3610,
Anal. Calcd. for C H N O: C, 78.42; H, 7.56. Found: C,
27 31
3
78.19; H, 7.45.
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(4-methyl-
pyperazin-1-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-1-one
(11b).
This compound was obtained as white prisms (ethyl
1
acetate-hexane) in 88%, mp 147-149°; H nmr: δ 1.63 (broad s,
-1
1
4H, 15-, 16-H), 2.09 (dd, 1H, 14-H, J = 12.9, 3.2 Hz), 2.23 (s,
7H, 15-, 16-, 17-H), 2.30 (t, 1H, 14-H, J = 12.9 Hz), 2.90 (dd,
1H, 4-H, J = 11.9, 3.0 Hz), 3.50 (d, 1H, 9-H, J = 14.3 Hz), 3.59
(s, 3H, 13-H), 5.14 (s, 1H, 3-H), 5.64-5.65 (m, 1H, 10-H), 5.80
(d, 1H, 9-H, J = 14.3 Hz), 5.92-5.93 (m, 1H, 11-H), 6.53-6.54
(m, 1H, 12-H), 6.95-7.00 (m, 1H, phenyl proton), 7.26-7.42 (m,
7H, phenyl protons), 8.21-8.24 (m, 1H, 8-H); ms: m/z 428
(molecular ion).
CO 1640 cm ; H nmr: δ 0.89 (t, 1H, -OH, J = 5.2 Hz), 2.93 (dd,
1H, 4-H, J = 10.3, 5.2 Hz), 3.27-3.34 (m, 1H, 14-H), 3.46 (s, 4H,
13-, 14- H), 3.53 (d, 1H, 9-H, J = 14.4 Hz), 4.82 (s, 1H, 3-H),
5.57-5.58 (m, 1H, 10-H), 5.76 (d, 1H, 9-H, J = 14.4 Hz), 5.82-
5.84 (m, 1H, 11-H), 6.44-6.45 (m, 1H, 12-H), 6.92-6.95 (m, 1H,
phenyl proton), 7.27-7.32 (m, 7H, phenyl protons), 8.12-8.16 (m,
1H, 8-H); ms: m/z 346 (molecular ion).
Anal. Calcd. for C H N O : C, 76.28; H, 6.40. Found: C,
22 22
2 2
Anal. Calcd. for C H N O: C, 75.67; H, 7.53. Found: C,
76.45; H, 6.66.
27 32
4
75.92; H, 7.66.
(±)-trans-2-Benzyl-1-oxo-3-(1-methyl-1H-pyrrol-2-yl)-4-tosy-
loxymethyl-1,2,3,4-tetrahydroisoquinoline (10).
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(4-phenyl-
pyperazin-1-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-1-one
(11c).
To a solution of 9 (19.78 g, 0.057 mole) in pyridine (100 mL)
kept at -5°, p-toluenesulfonyl chloride (21.81 g, 0.114 mole) was
added in portions. The reaction mixture was stirred at room tem-
perature for 15 hours, poured into water and extracted with ethyl
This compound was obtained as white prisms (ethyl acetate) in
66%, mp 132-134°; H nmr: δ 1.84-1.87 (m, 2H, 15-H), 2.14 (dd,
1

Jan-Feb 2002
233
New trans/cis Tetrahydroisoquinolines
1H, 14-H, J = 12.8, 3.0 Hz), 2.36 (t, 1H, 14-H, J = 12.8 Hz), 2.56-
2.58 (m, 2H, 15-H), 2.94-3.03 (m, 5H, 4-, 16-H), 3.50 (d, 1H, 9-H,
J = 14.2 Hz), 3.59 (s, 3H, 13-H), 5.23 (s, 1H, 3-H), 5.65-5.66 (m,
1H, 10-H), 5.83 (d, 1H, 9-H, J = 14.2 Hz), 5.92-5.93 (m, 1H,
11-H), 6.53-6.54 (m, 1H, 12-H), 6.71-6.90 (m, 3H, phenyl pro-
tons), 6.99-7.01 (m, 1H, phenyl proton), 7.26-7.41 (m, 9H, phenyl
protons), 8.23-8.25 (m, 1H, 8-H); ms: m/z 490 (molecular ion).
(dd, 1H, 14-H, J = 12.7 Hz), 2.16 (t, 1H, 14-H, J = 12.7 Hz), 2.36-
2.38 (m, 2H, 15-H), 2.62-2.66 (m, 4H, 16-H), 2.74 (dd, 1H, 4-H,
J = 11.9, 2.6 Hz), 3.30 (d, 1H, 9-H, J = 14.3 Hz), 3.39 (s, 3H,
13-H), 4.97 (s, 1H, 3-H), 5.46-5.47 (m, 1H, 10-H), 5.63 (d, 1H,
9-H, J = 14.3 Hz), 5.72-5.74 (m, 1H, 11-H), 6.34-6.35 (m, 1H,
12-H), 6.62-6.64 (m, 2H, phenyl protons), 6.75-6.79 (m, 3H,
phenyl protons), 7.06-7.21 (m, 7H, phenyl protons), 8.03-8.05
(m, 1H, 8-H); ms: m/z 508 (molecular ion).
Anal. Calcd. for C H N O: C, 78.34; H, 6.98. Found: C,
32 34
4
Anal. Calcd. for C H FN O: C, 75.56; H, 6.54. Found: C,
78.02; H, 7.08.
32 33
4
75.61; H, 6.65.
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(4-(2-
methoxyphenyl)pyperazin-1-yl)methyl]-1,2,3,4-tetrahydroiso-
quinolin-1-one (11d).
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(morpholin-
4-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-1-one (11h).
This compound was obtained as white prisms (ethyl
acetate-Hexane) in 63%, mp 147-148°; H nmr: δ 1.72 (broad s,
This compound was obtained as colorless crystals (ethyl
acetate) in 82%, mp 178-180°; H nmr: δ 1.73 (broad s, 2H,
1
1
2H, 15-H), 1.97 (dd, 1H, 14-H, J = 12.8, 3.2 Hz), 2.17 (t, 1H,
14-H, J = 12.8 Hz), 2.43 (broad s, 2H, 15-H), 2.62 (broad s, 4H,
16-H), 2.76 (dd, 1H, 4-H, J = 11.9, 2.6 Hz), 3.32 (d, 1H, 9-H, J =
14.3 Hz), 3.41 (s, 3H, 13-H), 3.66 (s, 3H, 17-H), 5.02 (s, 1H,
3-H), 5.46-5.47 (m, 1H, 10-H), 5.63 (d, 1H, 9-H, J = 14.3 Hz),
5.73-5.75 (m, 1H, 11-H), 6.34-6.36 (m, 1H, 12-H), 6.67-6.83 (m,
4H, phenyl protons), 7.07-7.21 (m, 8H, phenyl protons), 8.03-
8.06 (m, 1H, 8-H); ms: m/z 520 (molecular ion).
15-H), 2.11 (dd, 1H, 14-H, J = 12.8, 3.3 Hz), 2.27 (t, 1H, 14-H,
J = 12.8 Hz), 2.39 (broad s, 2H, 15-H), 2.91 (dd, 1H, 4-H, J =
11.9, 2.9 Hz), 3.41-3.45 (m, 4H, 16-H), 3.49 (d, 1H, 9-H, J = 14.2
Hz) 3.59 (s, 3H, 13-H), 5.17 (s, 1H, 3-H), 5.64-5.67 (m, 1H,
10-H), 5.82 (d, 1H, 9-H, J = 14.2 Hz), 5.92-5.93 (m, 1H, 11-H),
6.53-6.54 (m, 1H, 12-H), 6.96-6.98 (m, 1H, phenyl proton), 7.24-
7.42 (m, 7H, phenyl protons), 8.21-8.24 (m, 1H, 8-H) ; ms: m/z
415 (molecular ion).
Anal. Calcd. for C H N O : C, 76.12; H, 6.97. Found: C,
Anal. Calcd. for C H N O : C, 75.15; H, 7.03. Found: C,
33 36
4
2
26 29 3 2
76.02; H, 7.05.
75.20; H, 7.33.
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(4-(3-trifluo-
romethyl-phenyl)pyperazin-1-yl)methyl]-1,2,3,4-tetrahydroiso-
quinolin-one (11e).
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(2,6-
dimethyl-morpholin-4-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-
1-one (11i).
This compound was obtained as colorless prisms (ethyl
acetate) in 51%, mp 158-160°; H nmr: δ 1.66-1.70 (m, 2H,
This compound was obtained as white crystals (ethyl
acetate-hexane) in 53%, mp 150-152°; H nmr: δ 0.91-1.06 (m,
1
1
15-H), 1.96 (dd, 1H, 14-H, J = 12.8, 3.2 Hz), 2.19 (t, 1H, 14-H,
J = 12.8 Hz), 2.38-2.40 (m, 2H, 15-H), 2.75-2.78 (m, 5H, 4-,
16-H), 3.31 (d, 1H, 9-H, J = 14.3 Hz), 3.41 (s, 3H, 13-H), 4.98 (s,
1H, 3-H), 5.47-5.48 (m, 1H, 10-H), 5.64 (d, 1H, 9-H, J = 14.3
Hz), 5.74-5.76 (m, 1H, 11-H), 6.36-6.37 (m, 1H, 12-H), 6.81-
6.86 (m, 4H, phenyl protons), 7.15-7.23 (m, 8H, phenyl protons),
8.04-8.07 (m, 1H, 8-H); ms: m/z 558 (molecular ion).
6H, 17-H), 1.43-1.61 (m, 4H, 15-H), 1.97 (dd, 1H, 14-H, J =
12.7, 3.1 Hz), 2.19 (t, 1H, 14-H, J = 12.7 Hz), 2.85 (dd, 1H, 4-H,
J = 11.8, 2.7 Hz), 3.37-3.53 (m, 2H, 16-H), 3.40 (d, 1H, 9-H, J =
14.3 Hz), 3.51 (s, 3H, 13-H), 5.08 (s, 1H, 3-H), 5.56-5.60 (m, 1H,
10-H), 5.76 (d, 1H, 9-H, J = 14.3 Hz), 5.85-5.87 (m, 1H, 11-H),
6.46-6.47 (m, 1H, 12-H), 6.90-6.92 (m, 1H, phenyl proton), 7.22-
7.35 (m, 7H, phenyl protons), 8.15-8.17 (m, 1H, 8-H); ms: m/z
443 (molecular ion).
Anal. Calcd. for C H F N O: C, 70.95; H, 5.95. Found: C,
33 33
3 4
Anal. Calcd. for C H N O : C, 75.82, H, 7.50. Found: C,
70.90; H, 6.19.
28 33
3 2
76.17; H, 7.55.
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(4-(3-
chlorophenyl)pyperazin-1-yl)methyl]-1,2,3,4-tetrahydroiso-
quinolin-1-one (11f).
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(thiomor-
pholin-4-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-1-one (11j).
This compound was obtained as yellow crystals (ethyl acetate)
in 57%, mp 192-194°; H nmr: δ 2.00-2.04 (m, 2H, 15-H), 2.32
This compound was obtained as white crystals (ethyl acetate)
in 77%, mp 195-197°; H nmr: δ 1.71-1.75 (m, 2H, 15-H), 1.91-
1
1
(dd, 1H, 14-H, J = 12.7, 3.1 Hz), 2.54 (t, 1H, 14-H, J = 12.7 Hz)
2.72-2.75 (m, 2H, 15-H), 3.07-3.13 (m, 5H, 4-, 16-H), 3.67 (d,
1H, 9-H, J = 14.2 Hz), 3.77 (s, 3H, 13-H), 5.35 (s, 1H, 3-H), 5.84-
5.85 (m, 1H, 10-H), 6.02 (d, 1H, 9-H, J = 14.2 Hz), 6.11-6.12 (m,
1H, 11-H), 6.72-6.73 (m, 1H, 12-H), 6.93-7.01 (m, 3H, phenyl
protons), 7.19-7.59 (m, 9H, phenyl protons), 8.41-8.43 (m, 1H,
8-H); ms: m/z 524 (molecular ion).
1.99 (m, 2H, 14-H), 2.16-2.23 (m, 4H, 16-H), 2.43 (broad s, 2H,
15-H), 2.67 (dd, 1H, 4-H, J = 11.2, 3.5 Hz), 3.27 (d, 1H, 9-H, J =
14.3 Hz), 3.39 (s, 3H, 13-H), 4.86 (s, 1H, 3-H), 5.43-5.44 (m, 1H,
10-H), 5.62 (d, 1H, 9-H, J = 14.3 Hz), 5.71-5.72 (m, 1H, 11-H),
6.33-6.34 (m, 1H, 12-H), 6.74-6.76 (m, 1H, phenyl proton), 7.07-
7.26 (m, 7H, phenyl protons), 8.00-8.03 (m, 1H, 8-H); ms: m/z
431 (molecular ion).
Anal. Calcd. for C H ClN O: C, 73.20; H, 6.33. Found: C,
Anal. Calcd. for C H N OS: C, 72.36; H, 6.77. Found: C,
32 33
4
26 29 3
73.09; H, 6.45.
72.38; H, 6.77.
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(4-fluo-
rophenyl)pyperazin-1-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-
1-one (11g).
General Procedure for the Preparation of (±)-trans-2-Benzyl-3-
(1-methyl-1H-pyrrol-2-yl)-4-(N,N-disubstituted-aminomethyl)-
1,2,3,4-tetrahydroisoquinolines (12).
This compound was obtained as white crystals (ethyl acetate)
in 63%, mp 232-234°; H nmr: δ 1.64-1.68 (m, 2H, 15-H), 1.95
Lithium aluminium hydride (1.1 mmoles) was added in por-
tions to a solution of 11 (1 mmole) in 4 mL dry tetrahydrofuran
1

234
I. D. Kozekov, R. I. Koleva and M. D. Palamareva
Vol. 39
and the reaction mixture was refluxed 1-2 hours. After cooling,
water (4.4 mmoles) was added. The reaction mixture was stirred
for 30 minutes and dried (magnesium sulfate). The inorganic pre-
cipitate was filtered and washed with dichloromethane. The sol-
vent was removed from the filtrate and the product was purified
by chromatographic filtration or recrystallisation.
(d, each 1H, 1-H, J = 13.7 Hz), 3.80 (s, 2H, 9-H), 3.86 (s, 3H,
17-H), 4.67 (d, 1H, 3-H, J = 1.4 Hz), 5.52-5.53 (m, 1H, 10-H),
5.96-5.98 (m, 1H, 11-H), 6.52-6.53 (m, 1H, 12-H), 6.85-7.32 (m,
13H, phenyl protons); ms: m/z 506 (molecular ion).
Anal. Calcd. for C H N O: C, 78.23, H, 7.56. Found: C,
33 38
4
78.34; H, 7.56.
Compounds 12d,e,h were prepared also from tosylate 14 and
the corresponding secondary amine NuH by the general method
for synthesis of 11.
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(4-(3-trifluo-
romethyl-phenyl)pyperazin-1-yl)methyl]-1,2,3,4-tetrahydroiso-
quinoline (12e).
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(piperidin-1-
yl)methyl]-1,2,3,4-tetrahydroisoquinoline (12a).
This compound was obtained from 12e in 72% and from 14 in
35% as white crystals (ethanol), mp 124-126°; H nmr: δ 2.42
1
This compound was obtained as white crystals (ethyl acetate)
in 72%, mp 113-115°; H nmr: δ 1.32-1.45 (m, 6H, 16-H), 2.19
(dd, 1H, 14-H, J = 12.3, 3.6 Hz), 2.56-2.61 (m, 2H, 15-H), 2.77-
2.82 (m, 2H, 15-H), 3.01 (m, 1H, 4-H), 3.13-3.22 (m, 5H, 14-,
16-H), 3.50 (s, 3H, 13-H), 3.58 and 3.63 (d, each 1H, 1-H, J =
13.7 Hz), 3.84 (s, 2H, 9-H), 4.65 (d, 1H, 3-H, J = 1.6 Hz), 5.55-
5.64 (m, 1H, 10-H), 5.99-6.01 (m, 1H, 11-H), 6.55-6.56 (m, 1H,
12-H), 7.02-7.38 (m, 13H, phenyl protons); ms: m/z 544 (molec-
ular ion).
1
(dd, 1H, 14-H, J = 11.8, 3.1 Hz), 2.24 (broad s, 2H, 15-H), 2.47
(broad s, 2H, 15-H), 2.85 (d, 1H, 4-H, J = 11.0 Hz), 2.96 (t, 1H,
14-H, J = 11.8 Hz), 3.40 (s, 3H, 13-H), 3.45 and 3.52 (d, each 1H,
1-H, J = 13.7 Hz), 3.69 (s, 2H, 9-H), 4.59 (s, 1H, 3-H), 5.42-5.43
(m, 1H, 10-H), 5.87-5.89 (m, 1H, 11-H), 6.43-6.44 (m, 1H,
12-H), 6.91-7.07 (m, 4H, phenyl protons), 7.17-7.28 (m, 5H,
phenyl protons); ms: m/z 399 (molecular ion).
Anal. Calcd. for C H F N : C, 72.77, H, 6.48. Found: C,
33 35
3 4
72.92; H, 6.56.
Anal. Calcd. for C
81.20; H, 8.49.
H N : C, 81.16, H, 8.32. Found: C,
27 33 3
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(4-(3-
chlorophenyl)pyperazin-1-yl)methyl]-1,2,3,4-tetrahydroiso-
quinoline (12f).
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(4-methyl-
pyperazin-1-yl)methyl]-1,2,3,4-tetrahydroisoquinoline (12b).
This compound was obtained as white solvated with ethylac-
1
This compound was obtained as white crystals (ethyl acetate)
in 58%, mp 133-135°; H nmr: δ 2.26 (s, 3H, 17-H), 2.33 (dd,
etate crystals in 88%, mp 116-118°; H nmr: δ 2.57 (dd, 1H,
1
14-H, J = 12.3, 3.6 Hz), 2.71-2.75 (m, 2H, 15-H), 2.92-2.97 (m,
2H, 15-H), 3.17 (d, 1H, 4-H, J = 11.3 Hz), 3.27-3.38 (m, 5H, 14-,
16-H), 3.66 (s, 3H, 13-H), 3.76 (s, 2H, 1-H), 4.00 (s, 2H, 9-H),
4.81 (d, 1H, 3-H, J = 1.5 Hz), 5.71-5.73 (m, 1H, 10-H), 6.16-6.17
(m, 1H, 11-H), 6.72-6.73 (m, 1H, 12-H), 6.98-7.05 (m, 3H,
phenyl protons), 7.33-7.54 (m, 10H, phenyl protons); ms: m/z
510 (molecular ion). The nmr and ir spectra showed the corre-
sponding signals for ethyl acetate.
1H, 14-H, J = 12.2, 2.7 Hz), 2.43 (broad s, 4H, 15-, 16-H), 2.65
(broad s, 4H, 15-, 16-H), 2.94 (dd, 1H, 4-H, J = 11.1, 1.7 Hz),
3.10 (t, 1H, 14-H, J = 12.2 Hz), 3.50 (s, 3H, 13-H), 3.53 and 3.60
(d, each 1H, 1-H, J = 13.7 Hz), 3.77 (s, 2H, 9-H), 4.62 (d, 1H,
3-H, J = 1.7 Hz), 5.50-5.52 (m, 1H, 10-H), 5.96-5.97 (m, 1H,
11-H), 6.52-6.54 (m, 1H, 12-H), 6.99-7.04 (m, 1H, phenyl pro-
ton), 7.12-7.16 (m, 3H, phenyl protons), 7.26-7.36 (m, 5H,
phenyl protons); ms: m/z 414 (molecular ion).
Anal. Calcd. for C H ClN •1/3CH CO C H : C, 74.07, H,
32 35
4
3
2 2 5
Anal. Calcd. for C
H N : C, 78.22, H, 8.26. Found: C,
7.03. Found: C, 74.01; H, 7.36.
27 34 4
78.07; H, 8.41.
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(4-fluo-
rophenyl)pyperazin-1-yl)methyl]-1,2,3,4-tetrahydroisoquinoline
(12g).
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(4-phenyl-
pyperazin-1-yl)methyl]-1,2,3,4-tetrahydroisoquinoline (12c).
This compound was obtained as white crystals (ethyl acetate)
in 61%, mp 124-126°; H nmr: δ 2.41 (dd, 1H, 14-H, J = 12.2, 3.6
This compound was obtained as white crystals (ethanol) in
56%, mp 154-156°; H nmr: δ 2.65 (dd, 1H, 14-H, J = 12.1, 3.6
1
1
Hz), 2.55-2.60 (m, 2H, 15-H), 2.77-2.82 (m, 2H, 15-H), 3.00 (dd,
1H, 4-H, J = 11.0, 1.9 Hz), 3.08-3.21 (m, 5H, 14-, 16-H), 3.48 (s,
3H, 13-H), 3.59 (s, 2H, 1-H), 3.83 (s, 2H, 9-H), 4.67 (d, 1H, 3-H,
J = 1.3 Hz), 5.54-5.55 (m, 1H, 10-H), 5.99-6.00 (m, 1H, 11-H),
6.54-6.55 (m, 1H, 12-H), 6.85-6.95 (m, 3H, phenyl protons),
7.08-7.39 (m, 11H, phenyl protons); ms: m/z 476 (molecular
ion).
Hz), 2.79-2.83 (m, 2H, 15-H), 3.01-3.05 (m, 2H, 15-H), 3.22-
3.33 (m, 5H, 4-, 16-H), 3.42 (t, 1H, 14-H, J = 12.1 Hz), 3.73 (s,
3H, 13-H), 3.80 and 3.84 (d, each 1H, 1-H, J = 13.8 Hz), 4.06 (s,
2H, 9-H), 4.89 (s, 1H, 3-H), 5.77-5.79 (m, 1H, 10-H), 6.22-6.24
(m, 1H, 11-H), 6.78-6.79 (m, 1H, 12-H), 7.09-7.62 (m, 13H,
phenyl protons); ms: m/z 494 (molecular ion).
Anal. Calcd. for C H FN : C, 77.70, H, 7.13. Found: C,
32 35
4
Anal. Calcd. for C
H N : C, 80.63, H, 7.61. Found: C,
77.60; H, 7.25.
32 36 4
80.71; H, 7.53.
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(morpholin-
4-yl)methyl]-1,2,3,4-tetrahydroisoquinoline (12h).
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(4-(2-
methoxyphenyl)pyperazin-1-yl)methyl]-1,2,3,4-tetrahydroiso-
quinoline (12d).
This compound was obtained from 11h in 67% and from 14 in
1
47%, as white crystals (ethyl acetate-Hexane), mp 108-110°; H
This compound was obtained from 11d in 80% and from 14 in
44% as white crystals (ethyl acetate-hexane), mp 123-125°; H
nmr: δ 2.41 (dd, 1H, 14-H, J = 12.1, 3.6 Hz), 2.60 (broad s, 2H,
15-H), 2.72 (broad s, 2H, 15-H), 2.91-2.99 (m, 5H, 4-, 16-H),
3.16 (t, 1H, 14-H, J = 12.1 Hz), 3.48 (s, 3H, 13-H), 3.55 and 3.60
nmr: δ 2.31 (dd, 1H, 14-H, J = 12.2, 3.6 Hz), 2.32-2.37 (m, 2H,
15-H), 2.54-2.57 (m, 2H, 15-H), 2.90 (d, 1H, 4-H, J = 11.2 Hz),
3.04 (t, 1H, 14-H, J = 12.2 Hz), 3.46 (s, 3H, 13-H), 3.50 and 3.55
(d, each 1H, 1-H, J = 13.7 Hz), 3.53-3.63 (m, 4H, 16-H), 3.75 (s,
2H, 9-H), 4.57 (d, 1H, 3-H, J = 1.6 Hz), 5.47-5.48 (m, 1H, 10-H),
1

Jan-Feb 2002
235
New trans/cis Tetrahydroisoquinolines
5.92-5.94 (m, 1H, 11-H), 6.49-6.50 (m, 1H, 12-H), 7.00-7.13 (m,
4H, phenyl protons), 7.20-7.31 (m, 5H, phenyl protons); ms: m/z
401 (molecular ion).
Acknowlegement.
We thank Dr. Victor Sipido, Janssen Research Foundation,
Belgium for a financial support of the project.
Anal. Calcd. for C H N O: C, 77.77, H, 7.78. Found: C,
26 31
3
77.98; H, 7.81.
REFERENCES AND NOTES
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(2,6-
dimethylmorpholin-4-yl)methyl]-1,2,3,4-tetrahydroisoquino-
line (12i).
1
Present address: Vanderbilt University, Chemistry
Department, P. O. Box 1822-B, Nashville, TN 37235, USA.
This compound was obtained as yellow crystals (ethyl acetate)
in 52%, mp 174-176°; H nmr: δ 1.03-1.10 (m, 6H, 17-H), 1.63
*
E-mail address: mpalamareva@chem.uni-sofia.bg.
[1] T. Kametani, The Chemistry of the Isoquinoline
Alkaloids, Elsevier, New York, 1969.
[2] M. Shamma, J. Moniot, Isoquinoline Alkaloid Research:
1972-1977, Plenum Press. New York, 1978.
[3] N. Ito, Japan Patent 25, 971 (1968); Chem. Abstr., 70,
57685b (1969).
1
(t, 1H, 15-H, J = 11.5 Hz), 1.82 (t, 1H, 15-H, J = 11.5 Hz), 2.20
(dd, 1H, 14-H, J = 12.0, 3.4 Hz), 2.52 (d, 1H, 4-H, J = 11.1 Hz),
2.75-2.86 (m, 2H, 15-H), 2.97 (t, 1H, 14-H, J = 12.0 Hz), 3.38 (s,
3H, 13-H), 3.40-3.52 (m, 4H, 1-, 16-H), 3.72 (s, 2H, 9-H), 4.52
(s, 1H, 3-H), 5.42-5.45 (m, 1H, 10-H), 5.87-5.91 (m, 1H, 11-H),
6.44-6.45 (m, 1H, 12-H), 6.96-7.28 (m, 9H, phenyl protons); ms:
m/z 429 (molecular ion).
[4] G. Muller, French Patent M. 5, 415 (1967); Chem. Abstr.,
71, 91735y (1969).
[5] M. Haimova, M. Palamareva, B. Kurtev, S. Novkova and
S. Spassov, Chem. Ber., 103, 1347 (1970).
[6] M. A. Haimova, S. L. Spassov, M. D. Palamareva and B. J.
Kurtev, Chem. Ber., 104, 2601 (1971).
Anal. Calcd. for C H N O: C, 78.28, H, 8.21. Found: C,
78.10; H, 8.27.
28 35
3
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-[(thiomor-
pholin-4-yl)methyl]-1,2,3,4-tetrahydroisoquinoline (12j).
[7] M. A. Haimova, N. M. Mollov, S. C. Ivanova, A. I.
Dimitrova and V. I. Ognyanov, Tetrahedron, 33, 331 (1977).
[8] M. Cushman, J. Gentry and F. W. Dekow, J. Org. Chem.,
42, 1111 (1977).
[9] D. Sir Barton and D. Ollis, (Eds.) Comprehensive Organic
Chemistry, Pergamon Press, Oxford, Vol. 2, pp 407, 1979.
[10] E. R. Stanoeva and M. A. Haimova, Chem. Heterocycl.
Compd. (Engl. Transl.) 20, 1305 (1984), Review.
[11] M. Cushman and E. Madaj, J. Org. Chem., 52, 907 (1987),
and the references cited therin.
This compound was obtained as white crystals (ethyl acetate)
1
in 53%, mp 154-156°; H nmr: δ 2.51 (dd, 1H, 14-H, J = 12.2, 3.4
Hz), 2.66-2.79 (m, 6H, 15-, 16-H), 2.98-3.03 (m, 3H, 4-, 15-H),
3.12 (t, 1H, 14-H, J = 12.2 Hz), 3.61 (s, 3H, 13-H), 3.67 (s, 2H,
1-H), 3.92 (s, 2H, 9-H), 4.66 (s, 1H, 3-H), 5.61-5.62 (m, 1H,
10-H), 6.06-6.09 (m, 1H, 11-H), 6.65-6.66 (m, 1H, 12-H), 7.14-
7.46 (m, 9H, phenyl protons); ms: m/z 417 (molecular ion).
Anal. Calcd. for C H N S: C, 74.78, H, 7.48. Found: C,
26 31
3
[12] L. Fodor, J. Szabo, G. Bernath, P. Sohar, D. B. MacLean,
R W. Smith, I. Ninomiya and T. Naito, J. Heterocyclic Chem., 26,
333 (1989).
[13] F. T. Smith and R. V. Atigadda, J. Heterocyclic Chem., 28,
1813 (1991).
[14] J. Chen, D. Carlson, H. Weith, J. O′Brien, M. Goldman
and M. Cushman, Tetrahedron Lett., 33, 2275 (1992), and the refer-
ences cited therin.
[15] A. Georgieva, E. Stanoeva, S. Spassov, M. Haimova, N.
De Kimpe, M. Boelens, M. Keppens, A. Kemme and A. Mishnev,
Tetrahedron, 51, 6099 (1995), and the references cited therin.
[16] A. Georgieva, S. Spassov, E. Stanoeva, I. Topalova and C.
Chanev, J. Chem. Res. (S), 148 (1997).
74.76; H, 7.49.
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-hydroxy-
methyl-1,2,3,4-tetrahydroisoquinoline (13).
The completely reduced alcohol 13 was prepared from 8 in anal-
ogy to ref. [30] at reaction time 2 hours. It was obtained as white
-1
crystals (ethyl acetate) in 53%, mp 108-110°; ir: (OH) 3640 cm ;
1
H nmr: δ 1.57 (broad s, 1H, -OH), 2.98 (d, 1H, 4-H, J = 2.5 Hz),
3.32 (d, 1H, 9-H, J = 12.8 Hz), 3.52 and 3.65 (d, each 1H, 1-H, J =
15.5 Hz), 3.54 (s, 3H, 13-H), 3.71 (d, 1H, 9-H, J = 12.8 Hz), 3.92
and 4.11 (dd, each 1H, 14-H, J = 9.9, 3.5 Hz), 4.36 (d, 1H, 3-H, J =
2.5 Hz), 5.46-5.47 (m, 1H, 10-H), 5.88-5.90 (m, 1H, 11-H), 6.49-
6.50 (m, 1H, 12-H), 6.91-6.93 (m, 1H, phenyl proton), 7.08-7.25
(m, 8H, phenyl protons); ms: m/z 322 (molecular ion).
[17] J. Kiely, PCT Int. Appl. WO 16,428 (1997); Chem. Abstr.,
127, 34144f (1997).
[18] N. Yu, L. Bourel, B. Deprez and J. C. Gesquiere,
Tetrahedron Lett., 39, 829 (1998).
[19] Xi-Yin Xu, Guo-Wei Qin, Ren-Sheng Xu and Xing-Zu
Zhu, Tetrahedron, 54, 14179 (1998).
[20] M. Lebl, V. Krchnak, G. Ibrahim, J. Pires, Ch. Burger, Y.
Ni, Y. Chen, D. Podue, P. Mudra, V. Pokorny, P. Poncar and K.
Zenisek, Synthesis, 1971 (1999).
[21] N. Yu, R. Poulain and J. C. Gesquiere, Synlett, 355 (2000).
[22] B. Bonnaud, A. Carlessi and D. C. H. Bigg, J.
Heterocyclic Chem., 30, 257 (1993), and the references cited therin.
[23] V. Derdau and V. Snieckus, J. Org. Chem., 66, 1992
(2001).
Anal. Calcd. for C H N O: C, 79.48; H, 7.28. Found: C,
79.10; H, 7.27.
22 24
2
(±)-trans-2-Benzyl-3-(1-methyl-1H-pyrrol-2-yl)-4-tosyloxy-
methyl-1,2,3,4-tetrahydroisoquinoline (14).
The synthesis of the tosylate 14 from the parent alcohol 13 was
similar to the preparation of 10. The product was obtained as col-
1
orless crystals (ethyl acetate) in 63%, mp 126-128°; H nmr: δ
2.38 (s, 3H, 15-H), 3.25-3.36 (m, 2H, 4-, 9-H), 3.46-3.66 (m, 6H,
1-, 9-, 13-H), 4.17 and 4.64 (t, each 1H, 14-H, J = 9.8 Hz), 4.35
(d, 1H, 3-H, J = 2.0 Hz), 5.43-5.44 (m, 1H, 10-H), 5.92-5.95 (m,
1H, 11-H), 6.55-6.56 (m, 1H, 12-H), 6.93-7.36 (m, 11H, phenyl
protons), 7.76-7.80 (m, 2H, phenyl protons).
[24] E. Stanoeva, M. Haimova and Z. Radusheva, Commun.
Dept. Chem., Bulg. Acad. Sci., 14, 63 (1981), and the references cited
therin; Chem. Abstr. 96, 68779y (1982).
Anal. Calcd. for C H N O S: C, 71.58; H, 6.21. Found: C,
29 30
2 3
[25] N. S. Isaacs, Physical Organic Chemistry, Longman
71.42; H, 6.17.

236
I. D. Kozekov, R. I. Koleva and M. D. Palamareva
Vol. 39
Scientific & Technical, Essex, England, 1987, pp 131-153.
[26] M. Palamareva and S. Chorbadjiev, J. Chem. Soc., Perkin
Trans. 2, 961 (1996).
[28] V. Sipido, unpublished.
[29] M. D. Palamareva, R. I. Koleva and I. D. Kozekov, J. Liq.
Chrom. & Rel. Technol., 24, 1411 (2001).
[27] Y. Kita, K. Iio, A.Okajima, Y. Takeda, K. Kawaguchi, B.
A. Whelan and S. Akai, Synlett, 292 (1998), and the references cited
therin.
[30] M. Haimova, S. Mihovska, E. Stanoeva, K. Veleva, A.
Dimitrova, Commun. Dept. Chem., Bulg. Acad. Sci., 12, 325 (1979);
Chem. Abstr., 92, 163825m (1980).