Convenient synthesis of 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid derivatives via isocyanide-based, three-component reactions

Article abstract of DOI:10.1080/00397910903277920

The three-component reactions of 3,4-dihydroisoquinolines, isocyanides, and benzyl chloroformate furnished 2-benzyloxycarbonyl-1,2,3,4- tetrahydroisoquinoline-1-carboxamides in moderate to good yields. Hydrogenolysis or selective hydrolysis of the benzylo

Full text of DOI:10.1080/00397910903277920

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Convenient Synthesis of 1,2,3,4-
Tetrahydroisoquinoline-1-carboxylic Acid
Derivatives via Isocyanide-Based, Three-
Component Reactions
Ildikó Schuster a , László Lázár a & Ferenc Fülöp a
a Institute of Pharmaceutical Chemistry, University of Szeged,
Szeged, Hungary
Version of record first published: 26 Jul 2010
To cite this article: Ildikó Schuster, László Lázár & Ferenc Fülöp (2010): Convenient Synthesis of
1,2,3,4-Tetrahydroisoquinoline-1-carboxylic Acid Derivatives via Isocyanide-Based, Three-Component
Reactions, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 40:16, 2488-2498
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Synthetic Communications1, 40: 2488–2498, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903277920
CONVENIENT SYNTHESIS OF
1,2,3,4-TETRAHYDROISOQUINOLINE-1-CARBOXYLIC
ACID DERIVATIVES VIA ISOCYANIDE-BASED,
THREE-COMPONENT REACTIONS
´
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´
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Ildiko Schuster, Laszlo Lazar, and Ferenc Fu¨lop
Institute of Pharmaceutical Chemistry, University of Szeged, Szeged,
Hungary
The three-component reactions of 3,4-dihydroisoquinolines, isocyanides, and benzyl
chloroformate furnished 2-benzyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamides
in moderate to good yields. Hydrogenolysis or selective hydrolysis of the benzyloxycarbonyl
group provided 1,2,3,4-tetrahydroisoquinoline-1-carboxamides, further hydrolysis of which
resulted in the corresponding 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acids.
Keywords: a-Amino acids; isocyanides; isoquinolines; multicomponent reactions
INTRODUCTION
Thanks to their convenience, rapid scaffold construction, considerable molecu-
lar diversity, and high degree of atom economy, isocyanide-based multicomponent
reactions have received significant interest for both organic synthesis and drug
research.[1] In particular, the three- or four-component couplings of isocyanides
and various iminium species (Ugi reactions) resulting in a-acylaminocarboxamide
derivatives have been widely employed.[1,2]
Isocyanide-based multicomponent reactions are procedures that are often
applied for the synthesis of heterocyclic compounds, among them isoquinoline deri-
vatives.[3] Recent examples include the preparation of various 1,2-disubstituted
1,2-dihydro- or 1,2,3,4-tetrahydroisoquinolines via the coupling of the correspond-
ing isoquinolines, isocyanides, and carboxylic acids[4] or strong CH acids[5] or
chloroformate esters.[6] The hydrolysis of 2-acyl-1,2,3,4-tetrahydroisoquinoline-1-
carboxamides formed in Ugi three-component reactions provides a convenient
approach to 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acids,[4a] which, as confor-
mationally constrained a-amino acids, are of interest as potential building blocks
of modified peptides or other pharmacologically active compounds.[7]
As a continuation of our studies on the utilization of isocyanide-based multi-
component reactions in the synthesis of difunctional tetrahydroisoquinolines,[4a]
Received August 12, 2009.
Address correspondence to Prof. Ferenc Fulo¨p, Institute of Pharmaceutical Chemistry, University
¨
of Szeged, Eo¨tvo¨s u. 6, H-6720 Szeged, Hungary. E-mail: fulop@pharm.u-szeged.hu
2488

1,2,3,4-TETRAHYDROISOQUINOLINE-1-CARBOXYLIC ACID DERIVATIVES
2489
our present aim was to apply benzyl chloroformate as an activating agent to generate
reactive dihydroisoquinolinium salts for coupling with isocyanides. It was expected
that presence of the readily and selectively removable N-benzyloxycarbonyl
(N-Cbz) group in the products would promote access to 2-unsubstituted
1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid derivatives.
RESULTS AND DISCUSSION
[6a]
´
On the basis of the method described by Dıaz et al.,
who generated
acylazinium salts from nitrogen-containing aromatic heterocycles for isocyanide
coupling using chloroformates, a mixture of 6,7-dimethoxy-3,4-dihydroisoquinoline
(1a),[8] benzyl chloroformate, and cyclohexyl isocyanide was allowed to react in
CHCl3 at room temperature. The aqueous quenching during the workup extraction
gave diamide 2a in 89% yield. Similar reactions of 1a with benzyl or tert-butyl iso-
cyanide furnished the corresponding 2b and 2c in somewhat lesser yields. To test
=
the scope and limitations of the C N component, couplings with 6,7-unsubstituted
(1b),[9] 6,7-diethoxy- (1c),[10] and 6,7-methylenedioxy-3,4-dihydroisoquinoline (1d)[11]
were also performed and resulted in 2d–f in moderate yields (Scheme 1). As Ugi reac-
tions are known to proceed in aqueous media,[12] coupling of 1a with benzyl
chloroformate and cyclohexyl isocyanide was also attempted in water, but 2a was
isolated in only poor yield (24%).
Scheme 1. Reagents and conditions: (i) PhCH2OCOCl, isocyanide, CHCl3, rt, 5–24 h, then H2O, rt, 30 min
(46–89%); (ii) (1) 33% HBr in AcOH, 30 min, rt, (2) NaOH (83–95%); (iii) H2 (1 atm), Pd=C, EtOH, rt,
4–6 h (61–89%); (iv) 10% HCl, reflux, 20–25 h (62–76%); (v) 10% HCl, reflux, 20–65 h (36–76%).

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I. SCHUSTER, L. LAZAR, AND F. FULOP
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2490
As common methods for removal of the benzyl carbamate group,[13] hydrogeno-
lysis and acidic hydrolysis were investigated for 2a–f (Scheme 1). Hydrogenation of
2a–f under atmospheric pressure in the presence of palladium on charcoal catalyst
resulted in the corresponding 2-unsubstituted 1,2,3,4-tetrahydroisoquinoline-1-carbox-
amides 3a–f in good to moderate yields (61–89%). Somewhat better yields (83–95%)
were achieved from the reactions of 2a–f with 33% HBr in acetic acid, with subsequent
alkaline treatment to liberate the free bases 3a–f from the hydrobromide salts formed.
When 2a,d and 3a,d,e were subjected to acidic hydrolysis in refluxing 10% aqueous
HCl, the hydrochloride salts of the corresponding 1,2,3,4-tetrahydroisoquinoline-1-
carboxylic acids 4a–c were obtained (Scheme 1). Compounds 3a,d,e underwent
hydrolysis in a shorter time and with better yields than the corresponding reactions of
2a,d. Hydrolysis of the 6,7-methylenedioxy derivatives 2f and 3f led to complex mixtures
from which the corresponding amino acid could not be isolated; this was probably due to
the sensitivity of the 1,3-dioxolane moiety to the harsh reaction conditions.
To test the effect of a 3-methyl substituent on the starting dihydroisoquinoline
and to devise a procedure for the synthesis of 3-methyl-substituted tetrahydroiso-
quinoline-1-carboxylic acid derivatives, coupling of 3-methyl-6,7-dimethoxy-3,4-
dihydroisoquinoline (5)[14] was also attempted (Scheme 2). The integrals of the 3-H
Scheme 2. Reagents and conditions: (i) PhCH2OCOCl, cyclohexyl isocyanide, CHCl3, rt, 24 h, then H2O,
rt, 30 min, followed by fractional crystallization (6a: 31%, 6b: 44%); (ii) H2 (1 atm), Pd=C, EtOH, rt, 6 h
(56–68%); (iii) 10% HCl, reflux, 40 h (30–32%).

1,2,3,4-TETRAHYDROISOQUINOLINE-1-CARBOXYLIC ACID DERIVATIVES
2491
multiplets in the 1H NMR spectrum of the crude product did not reveal any
diastereoselectivity in the formation of the cis and trans isomers of the corresponding
1,3-disubstituted tetrahydroisoquinolines (6a,b). The steric hindrance caused by the
3-Me substituent resulted in the total yields for 6a and 6b being less than that observed
for 2a. Diastereomers 6a and 6b were separated by fractional crystallization, and their
relative configurations were determined by nuclear Overhauser effect spectroscopy
(NOESY) measurements, where NOE interactions were detected between 3-Me and
NH in 6a and between 3-Me and 1-H in 6b. Removal of the N-Cbz group in 6a,b was
achieved by hydrogenolysis afforded the corresponding diastereomeric carboxamides
7a,b. When either 7a or 7b was submitted to acidic hydrolysis in refluxing 10% HCl,
the reaction was accompanied by a total loss of diastereomeric purity, and a 1:1 mixture
of cis- and trans-6,7-dimethoxy-3-methyl-1,2,3,4-tetrahydroisoquinoline-1-carboxylic
acid hydrochloride (8) was obtained. This phenomenon can be rationalized by the ease
with which tetrahydroisoquinoline-1-carboxylic acids undergo racemization in acidic
medium.[4a,7d] All of our efforts to separate the diastereomers of 8 have so far failed.
In conclusion, our results indicate that the readily available 3,4-dihydroisoqui-
nolines are convenient starting materials for the synthesis of 1,2,3,4-
tetrahydroisoquinoline-1-carboxamides, via coupling with benzyl chloroformate
and isocyanides, and subsequent selective removal of the N-Cbz substituent of the
Ugi-type intermediates. Further hydrolysis of the carboxamides provides the
corresponding tetrahydroisoquinoline-1-carboxylic acids.
EXPERIMENTAL
Melting points were recorded on a Kofler hot-plate microscope apparatus and
are uncorrected. For column chromatography, silica gel 60 (0.063–0.200 mm) was
used, and for thin-layer chromatography (TLC), Merck Kieselgel 60 F254 plates were
used. 1H NMR spectra were recorded at 400 MHz in dimethylsulfoxide (DMSO-d6),
CDCl3, or D2O at ambient temperature on a Bruker Avance DRX 400 spectrometer.
Chemical shifts are given in d (ppm) relative to tetramethylsilane (DMSO or CDCl3)
or to sodium 3-(trimethylsilyl)propanoate-d4 (D2O) as internal standards.
General Procedure for the Preparation of Compounds 2a–f and 6a,b
A solution of the corresponding 3,4-dihydroisoquinoline (1, 3 mmol), 2
equivalents of benzyl chloroformate (6 mmol), and 1.2 equivalents of the appropriate
isocyanide (3.6 mmol) in CHCl3 (45 ml) was stirred at room temperature until TLC
indicated complete consumption of the starting materials (5–24 h). Water (10 ml) was
then added, and the mixture was stirred for 30 min. The layers were separated, and
the aqueous phase was washed twice with CHCl3. The combined organic layers were
dried (Na2SO4) and evaporated. The residue was purified by column chromato-
graphy on silica gel, with CHCl3 as eluent.
For 6a,b, chromatographic purification resulted in an oily diastereomeric
mixture, which crystallized on treatment with Et2O. The crystalline product was
1
filtered off, and its H NMR spectrum showed it to be diastereomerically pure 6b.
Evaporation of the filtrate afforded diastereomerically pure 6a.

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I. SCHUSTER, L. LAZAR, AND F. FULOP
2492
Selected Data
2-Benzyloxycarbonyl-1-cyclohexylcarbamoyl-6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinoline (2a). Yield: 1.21 g (89%), a white crystalline solid, mp
1
153–154.5 ꢀC; H (CDCl3): d 7.37 (5H, m, Ph), 6.93 and 6.80 (rotamers in a ratio
of 52:48, 1H, br s, C6H2), 6.61 (1H, s, C6H2), 6.16 and 5.75 (rotamers in a ratio
of 57:43, 1H, br s, NH), 5.41 (1H, br s, CHN), 5.21 (2H, br s, CH2Ph), 3.97 (1H,
m, CH), 3.86 (3H, s, OCH3), 3.86 (3H, s, OCH3), 3.70 (1H, m, CH), 2.80 (2H, m,
CH2CH2N), 1.78–1.12 (10H, m, 5 ꢁ CH2) ppm. Anal. calcd. for C26H32N2O5: C,
69.01; H, 7.13; N, 6.19. Found: C, 68.87; H, 7.01; N, 6.33.
1-Benzylcarbamoyl-2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinoline (2b). Yield: 0.69 g (50%), a white crystalline solid, mp
169–172 ꢀC; 1H (CDCl3): d 8.81–8.77 (1H, m, NH), 7.39–7.11 (11H, m, 11 ꢁ CH aro-
matic protons), 6.77 (1H, s, C6H2), 5.36 (1H, s, CHN), 5.13 (2H, s, CH2Ph), 4.32
(1H, dt, J ¼ 6.0, 15.5 Hz, CH2N), 4.18 (1H, dq, J ¼ 5.0, 15.0 Hz, CH2N), 3.93–3.86
(1H, m, CH2NH), 3.72 (3H, s, OCH3), 3.64 (3H, s, OCH3), 3.62 (1H, m, CH2NH),
2.93–2.87 (1H, m, CH2CH2N), 2.73–2.66 (1H, m, CH2CH2N) ppm. Anal. calcd. for
C27H28N2O5: C, 70.42; H, 6.13; N, 6.08. Found: C, 70.38; H, 6.02; N, 6.20.
2-Benzyloxycarbonyl-6,7-dimethoxy-1-tert-butylcarbamoyl-1,2,3,4-tetra-
hydroisoquinoline (2c). Yield: 1.07 g (84%), a white crystalline solid, mp
1
136–139 ꢀC; H (DMSO-d6): 7.87 (1H, s, NH), 7.42–7.32 (5H, m, Ph), 7.15 (1H, s,
C6H2), 6.74 (1H, s, C6H2), 5.28 (1H, s, CHN), 5.11 (2H, m, CH2Ph), 3.89–3.79
(1H, m, CH2N), 3.74 (1H, m, CH2N), 3.72 (3H, s, OCH3), 3.70 (3H, s, OCH3),
2.87–2.81 (1H, m, CH2CH2N), 2.70–2.63 (1H, m, CH2CH2N), 1.15 (9H, s, 3 ꢁ CH3)
ppm. Anal. calcd. for C24H30N2O5: C, 67.59; H, 7.09; N, 6.57. Found: C, 67.73; H,
7.21; N, 6.47.
2-Benzyloxycarbonyl-1-cyclohexylcarbamoyl-1,2,3,4-tetrahydroisoqui-
noline (2d). Yield: 0.55 g (47%), a white crystalline solid, mp 126–127 ꢀC; 1H
(DMSO-d6): d 8.15 (1H, d, J ¼ 7.6 Hz, NH), 7.49–7.18 (9H, m, 9 ꢁ CH aromatic pro-
tons), 5.39 (1H, s, CHN), 5.22–5.03 (2H, m, CH2Ph), 3.97–3.89 (1H, m, CH),
3.69–3.62 (1H, m, CH2N), 3.42–3.37 (1H, m, CH2N), 3.01–2.98 (1H, m, CH2CH2N),
2.79–2.72 (1H, m, CH2CH2N), 1.72–1.07 (10H, m, 5 ꢁ CH2) ppm. Anal. calcd. for
C24H28N2O3: C, 73.44; H, 7.19; N, 7.14. Found: C, 73.69; H, 7.31; N, 6.98.
2-Benzyloxycarbonyl-1-cyclohexylcarbamoyl-6,7-diethoxy-1,2,3,4-tetra-
hydroisoquinoline (2e). Yield: 0.90 g (62%), a white crystalline solid, mp
171–174 ꢀC; 1H (DMSO-d6): d 8.09 (1H, d, J ¼ 7.8 Hz, NH), 7.37–7.07 (5H, m,
Ph), 7.13 (1H, s, C6H2), 6.73 (1H, s, C6H2), 5.28–5.01 (3H, m, CHN and CH2Ph),
3.98 (4H, q, J ¼ 7.0 Hz, 2 ꢁ CH2CH3), 3.99–3.83 (1H, m, CH), 3.70–3.61 (1H, m,
CH2N), 3.43 (1H, m, CH2N), 2.89–2.84 (1H, m, CH2CH2N), 2.68–2.61 (1H, m,
CH2CH2N), 1.60–1.09 (10H, m, 5 ꢁ CH2), 1.30 (6H, t, J ¼ 7.0 Hz, 2 ꢁ CH2CH3)
ppm. Anal. calcd. for C28H36N2O5: C, 69.98; H, 7.55; N, 5.83. Found: C, 70.13;
H, 7.68; N, 5.71.
2-Benzyloxycarbonyl-1-cyclohexylcarbamoyl-6,7-methylenedioxy-1,2,3,4-
tetrahydroisoquinoline (2f). Yield: 0.61 g (46%), a white crystalline solid, mp
150–152 ꢀC; 1H (DMSO-d6): d 8.02 (1H, d, J ¼ 7.4 Hz, NH), 7.38–7.30 (5H, m,

1,2,3,4-TETRAHYDROISOQUINOLINE-1-CARBOXYLIC ACID DERIVATIVES
2493
Ph), 7.05 (1H, s, C6H2), 6.74 (1H, s, C6H2), 5.96 (2H, s, OCH2O), 5.29–5.01 (3H, m,
CHN and CH2Ph), 3.88 (1H, m, CH cyclohexyl), 3.57 (1H, m, CH2N), 3.41 (1H, m,
CH2N), 2.90 (1H, m, CH2CH2N), 2.66 (1H, m, CH2CH2N), 1.59–1.07 (10H,
m, 5 ꢁ CH2) ppm. Anal. calcd. for C25H28N2O5: C, 68.79; H, 6.47; N, 6.42. Found:
C, 68.65; H, 6.39; N, 6.58.
(1Rꢂ,3Rꢂ)-2-Benzyloxycarbonyl-1-cyclohexylcarbamoyl-6,7-dimethoxy-
3-methyl-1,2,3,4-tetrahydroisoquinoline (6a). Yield: 0.43 g (31%), a yellow oil;
1H (DMSO–d6): d 7.95 (1H, br s, NH), 7.37–7.31 (5H, m, Ph), 7.08 (1H, s, C6H2),
6.75 (1H, s, C6H2), 5.37 (1H, br s, CHN), 5.10 (2H, s, CH2Ph), 3.72 (3H, s,
OCH3), 3.69 (3H, s, OCH3), 3.49–3.47 (1H, m, CHCH3), 3.33 (1H, m, CH),
2.84 (1H, dd, J ¼ 5.4, 15.3 Hz, CH2CH2N), 2.68 (1H, dd, J ¼ 5.6, 15.3 Hz,
CH2CH2N), 1.65–1.09 (10H, m, 5 ꢁ CH2), 1.23 (3H, d, J ¼ 4.5 Hz, CHCH3)
ppm. Anal. calcd. for C27H34N2O5: C, 69.50; H, 7.35; N, 6.00. Found: C, 69.61;
H, 7.46; N, 5.87.
(1Sꢂ,3Rꢂ)-2-Benzyloxycarbonyl-1-cyclohexylcarbamoyl-6,7-dimethoxy-
3-methyl-1,2,3,4-tetrahydroisoquinoline (6b). Yield: 0.52 g (44%), a white crys-
1
talline solid, mp 190–192 ꢀC; H (CDCl3): d 7.83 (1H, m, NH), 7.36–7.29 (6H, m,
6 ꢁ CH aromatic protons), 6.75 (1H, s, C6H2), 5.19–5.01 (3H, m, CHN and CH2Ph),
4.52–4.50 (1H, m, CHCH3), 3.73 (3H, s, OCH3), 3.71 (3H, s, OCH3), 3.35 (1H, m,
CH), 2.44 (1H, m, CH), 1.51–0.97 (10H, m, 5 ꢁ CH2), 0.87 (3H, d, J ¼ 6.3 Hz,
CHCH3) ppm. Anal. calcd. for C27H34N2O5: C, 69.50; H, 7.35; N, 6.00. Found:
C, 69.65; H, 7.51; N, 5.92.
General Procedure for the Preparation of 3a–f by Hydrolysis of 2a–f
A mixture of 2 (1 mmol) and 33% HBr in AcOH (5 mL) was heated gently in a
flask equipped with a CaCl2 tube, with occasional shaking, until all of the substance
had dissolved. The bubbling solution was left to stand at ambient temperature for
30 min, and Et2O (10 mL) was then added. The crystals of the hydrobromides (3)
that formed were filtered off and washed with a mixture of MeOH and Et2O. The
dried crude crystalline product was dissolved in 95% aqueous MeOH, and Et2O
was then added until crystallization started.
Selected Data
N-Cyclohexyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxa-
mide hydrobromide (3a.HBr). Yield: 0.34 g (88%), a white crystalline solid, mp
1
262–265 ꢀC; H (D2O): 7.02 (1H, s, C6H2), 6.94 (1H, s, C6H2), 5.12 (1H, s, CHN),
3.93 (3H, s, OCH3), 3.89 (3H, s, OCH3), 3.83–3.77 (2H, m, CH2N and CH), 3.52
(1H, ddd, J1 ¼ 5.5 Hz, J2 ¼ 8.8 Hz, J3 ¼ 12.6 Hz, CH2N), 3.20 (1H, ddd,
J1 ¼ 5.9 Hz, J2 ¼ 8.8 Hz, J3 ¼ 17.1 Hz, CH2CH2N), 3.08 (1H, dt, J1 ¼ 5.4 Hz,
J2 ¼ 17.4 Hz, CH2CH2N), 1.95–1.38 (10H, m, 5 ꢁ CH2) ppm. Anal. calcd. for
C18H27BrN2O3: C, 54.14; H, 6.82; N, 7.02. Found: C, 54.20; H, 6.89; N, 6.97.
N-Benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide
hydrobromide (3b.HBr). Yield: 0.39 g (95%), a white crystalline solid, mp

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I. SCHUSTER, L. LAZAR, AND F. FULOP
2494
1
251–254 ꢀC; H (D2O): d 7.46–7.36 (5H, m, 5 ꢁ CH aromatic protons), 7.00 (1H, s,
C6H2), 6.80 (1H, s, C6H2), 5.21 (1H, s, CHN), 4.69 (1H, d, J ¼ 14.8 Hz, CH2Ph), 4.39
(1H, d, J ¼ 14.8 Hz, CH2Ph), 3.90 (3H, s, OCH3), 3.78–3.72 (1H, m, CH2N), 3.64
(3H, s, OCH3), 3.55–3.49 (1H, m, CH2N), 3.17–3.05 (2H, m, CH2CH2N) ppm.
Anal. calcd. for C19H23BrN2O3: C, 56.03; H, 5.69; N, 6.88. Found: C, 56.12; H,
5.76; N, 6.80.
N-(tert-Butyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxa-
mide hydrobromide (3c.HBr). Yield: 0.33 g (88%), a white crystalline solid, mp
251–253 ꢀC; 1H (D2O): d 7.03 (1H, s, C6H2), 6.96 (1H, s, C6H2), 5.07 (1H, s,
CHN), 3.93 (3H, s, OCH3), 3.91 (3H, s, OCH3), 3.80 (1H, dt, J1 ¼ 5.7 Hz,
J2 ¼ 12.5 Hz, CH2N), 3.52–3.48 (1H, m, CH2N), 3.20 (1H, dt, J1 ¼ 7.9 Hz,
J2 ¼ 17.5 Hz, CH2CH2N), 3.08 (1H, dt, J1 ¼ 4.9 Hz, J2 ¼ 17.6 Hz, CH2CH2N), 1.46
(9H, s, 3 ꢁ CH3) ppm. Anal. calcd. for C16H25BrN2O3: C, 54.14; H, 6.82; N, 7.02.
Found: C, 53.95; H, 6.76; N, 7.13.
N-Cyclohexyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamide hydrobro-
1
mide (3d.HBr). Yield: 0.29 g (86%), a white crystalline solid, mp 148–152 ꢀC; H
(D2O): d 7.51–7.42 (4H, m, C6H4), 5.21 (1H, s, CHN), 3.84–3.73 (2H, m, CH2N),
3.59–3.52 (1H, m, CH), 3.27 (1H, dt, J1 ¼ 7.0 Hz, J2 ¼ 17.7 Hz, CH2CH2N), 3.16
(1H, dt, J1 ¼ 5.5 Hz, J2 ¼ 17.7 Hz, CH2CH2N), 1.95–1.23 (10H, m, 5 ꢁ CH2) ppm.
Anal. calcd. for C16H23BrN2O3: C, 56.64; H, 6.83; N, 8.26. Found: C, 56.52; H,
6.76; N, 8.35.
N-Cyclohexyl-6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxa-
mide hydrobromide (3e.HBr). Yield: 0.35 g (83%), a white crystalline solid, mp
272–274 ꢀC; 1H (D2O): d 7.02 (1H, s, C6H2), 6.95 (1H, s, C6H2), 5.10 (1H, s,
CHN), 4.23–4.11 (4H, m, 2 ꢁ CH2CH3), 3.82–3.75 (2H, m, CH2N), 3.54–3.48 (1H,
m, CH), 3.22–3.03 (2H, m, CH2CH2N), 1.95–1.22 (10H, m, 5 ꢁ CH2), 1.45 (6H, t,
J ¼ 7.0 Hz, 2 ꢁ CH2CH3) ppm. Anal. calcd. for C20H31BrN2O3: C, 56.21; H, 7.31;
N, 6.55. Found: C, 56.12; H, 7.26; N, 6.49.
N-Cyclohexyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline-1-
carboxamide hydrobromide (3f.HBr). Yield: 0.32 g (84%), a white crystalline
1
solid, mp 226–230 ꢀC; H (D2O): d 6.89 (1H, s, C6H2), 6.88 (1H, s, C6H2), 6.07
(1H, s, OCH2O), 6.05 (1H, s, OCH2O), 5.10 (1H, s, CHN), 3.76 (2H, m, CH2N),
3.53–3.46 (1H, m, CH), 3.15 (1H, dt, J1 ¼ 7.2 Hz, J2 ¼ 17.4 Hz, CH2CH2N), 3.06
(1H, dt, J1 ¼ 5.5 Hz, J2 ¼ 17.4 Hz, CH2CH2N), 1.96–1.24 (10H, m, 5 ꢁ CH2) ppm.
Anal. calcd. for C17H23BrN2O3: C, 53.27; H, 6.05; N, 7.31. Found: C, 53.42; H,
6.16; N, 7.19.
General Procedure for the Preparation of 3a–f and 7a,b by
Hydrogenolysis of 2a–f and 6a,b
A mixture of 2 (1 mmol), 10% Pd=C (0.3 g), and EtOH (50 ml) was stirred
under a H2 atmosphere at ambient temperature until TLC indicated complete
conversion of the starting material (4–6 h). The catalyst was then filtered off, and
the solution was evaporated. The residue was purified by column chromatography
on silica gel, with EtOAc as eluent.

1,2,3,4-TETRAHYDROISOQUINOLINE-1-CARBOXYLIC ACID DERIVATIVES
2495
Selected Data
N-Cyclohexyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxa-
mide (3a). Yield: 0.46 g (89%), a white crystalline solid, mp 138–140 ꢀC; 1H
(CDCl3): d 7.11 (1H, s, C6H2), 7.07 (1H, d, J ¼ 7.0 Hz, NH), 6.55 (1H, s, C6H2),
4.43 (1H, s, CHN), 3.86 (3H, s, OCH3), 3.84 (3H, s, OCH3), 3.77–3.68 (1H, m,
CH), 3.05 (2H, t, J ¼ 5.8 Hz, CH2N), 2.77 (1H, td, J ¼ 6.0, 15.8 Hz, CH2CH2N),
2.66 (1H, td, J ¼ 5.5, 15.8 Hz, CH2CH2N), 1.91–1.06 (10H, m, 5 ꢁ CH2) ppm. Anal.
calcd. for C18H26N2O3: C, 67.90; H, 8.23; N, 8.80. Found: C, 67.76; H, 8.11; N, 8.92.
N-Benzyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide
(3b). Yield: 0.69 g (75%), a white crystalline solid, mp 159–160 ꢀC (lit.[15] mp
1
160–162 ꢀC); H (CDCl3): d 7.56 (1H, br s, NH), 7.26–7.22 (5H, m, Ph), 7.07 (1H,
s, C6H2), 6.56 (1H, s, C6H2), 4.61 (1H, s, CHN), 3.83 (6H, s, 2 ꢁ OCH3), 3.08
(2H, m, CH2), 2.77–2.68 (2H, m, CH2CH2N), 20.4 (2H, s, CH2Ph) ppm. Anal. calcd.
for C19H22N2O3: C, 69.92; H, 6.79; N, 8.58. Found: C, 70.05; H, 6.87; N, 8.43.
N-(tert-Butyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxa-
mide (3c). Yield: 0.47 g (62%), a white crystalline solid, mp 139–142 ꢀC; 1H
(CDCl3): d 7.07 (1H, s, C6H2), 7.06 (1H, s, NH), 6.56 (1H, s, C6H2), 4.34 (1H, s,
CHN), 3.85 (3H, s, OCH3), 3.84 (3H, s, OCH3), 3.06 (2H, br s, CH2N), 2.80–2.62
(2H, m, CH2CH2N), 1.32 (9H, s, 3 ꢁ CH3) ppm. Anal. calcd. for C16H24N2O3: C,
65.73; H, 8.27; N, 9.58. Found: C, 65.89; H, 8.42; N, 9.39.
N-Cyclohexyl-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (3d). Yield:
0.38g (61%), a white crystalline solid, mp 138–139 ꢀC; 1H (CDCl3): d 7.45–7.08
(4H, m, 4 ꢁ CH aromatic protons), 6.99 (1H, d, J ¼ 6.8 Hz, NH), 4.64 (1H, s,
CHN), 3.79–3.69 (1H, m, CH), 3.16 (1H, m, CH2N), 3.07 (1H, m, CH2N), 2.89
(1H, m, CH2CH2N), 2.78 (1H, m, CH2CH2N), 1.90–1.05 (10H, m, 5 ꢁ CH2) ppm.
Anal. calcd. for C16H22N2O: C, 74.38; H, 8.58; N, 10.84. Found: C, 74.51; H, 8.63;
N, 10.79.
N-Cyclohexyl-6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide
1
(3e). Yield: 0.32 g (66%), a white crystalline solid, mp 147–148 ꢀC; H (CDCl3): d
7.00 (1H, s C6H2), 6.97 (1H, br s, NH), 6.57 (1H, s, C6H2), 4.52 (1H, s, CHN),
4.09–4.03 (4H, m, 2 ꢁ CH2CH3), 3.77–3.70 (1H, m, CH), 3.13–3.02 (2H, m,
CH2N), 2.81–2.74 (1H, m, CH2CH2N), 2.70–2.64 (1H, m, CH2CH2N), 1.89–1.03
(10H, m, 5 ꢁ CH2), 1.44–1.40 (6H, m, 2 ꢁ CH2CH3) ppm. Anal. calcd. for
C20H30N2O3: C, 69.33; H, 8.73; N, 8.09. Found: C, 69.57; H, 8.86; N, 7.89.
N-Cyclohexyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline-1-
carboxamide (3f). Yield: 0.38 g (74%), a white crystalline solid, mp 138–140 ꢀC;
1H (CDCl3): d 6.99 (1H, s, C6H2), 6.53 (1H, s, C6H2), 5.90 (1H, s, OCH2O), 5.89
(1H, s, OCH2O), 4.59 (1H, s, CHN), 3.71–3.69 (1H, m, CH), 3.20–3.05 (2H, m,
CH2N), 2.83–2.67 (2H, CH2CH2N), 1.88–1.09 (5 ꢁ CH2) ppm. Anal. calcd. for
C17H22N2O3: C, 67.53; H, 7.33; N, 9.26. Found: C, 67.41; H, 7.18; N, 9.39.
(1Rꢂ,3Rꢂ)-N-Cyclohexyl-6,7-dimethoxy-3-methyl-1,2,3,4-tetrahydroiso-
quinoline-1-carboxamide (7a). Yield: 0.46 g (56%), a white crystalline solid, mp
1
160–163 ꢀC; H (CDCl3): d 7.09 (1H, s, C6H2), 6.94 (1H, d, J ¼ 7.7 Hz, NH), 6.45

´ ´
¨
¨
I. SCHUSTER, L. LAZAR, AND F. FULOP
2496
(1H, s, C6H2), 4.53 (1H, s, CHN), 3.76 (6H, s, 2 ꢁ OCH3), 3.68–3.58 (1H, m, CH),
3.03–2.95 (1H, m, CHCH3), 2.53–2.40 (2H, m, CH2N), 1.82–0.97 (10H, m, 5 ꢁ CH2),
), 1.17 (3H, d, J ¼ 6.0 Hz, CHCH3) ppm. Anal. calcd. for C19H28N2O3: C, 68.65; H,
8.49; N, 8.43. Found: C, 68.55; H, 8.63; N, 8.39.
(1Sꢂ,3Rꢂ)-N-Cyclohexyl-6,7-dimethoxy-3-methyl-1,2,3,4-tetrahydroiso-
quinoline-1-carboxamide (7b). Yield: 0.66 g (68%), a white crystalline solid, mp
1
161–162.5 ꢀC; H (CDCl3): d 7.04 (1H, d, J ¼ Hz, NH), 6.94 (1H, s, C6H2), 6.56
(1H, s, C6H2), 6.43 (1H, br s, NH), 4.53 (1H, s, CHN), 3.86 (3H, s, OCH3), 3.85
(3H, s, OCH3), 3.78–3.71 (1H, m, CH), 3.12–3.06 (1H, m, CHCH3), 2.74 (1H, dd,
J ¼ 4.0, 16.2 Hz, CH2N), 2.46 (1H, dd, J ¼ 10.0, 16.2 Hz, CH2N), 1.86–1.09 (10H,
m, 5 ꢁ CH2), 1.24 (3H, d, J ¼ 6.4 Hz, CHCH3) ppm. Anal. calcd. for C19H28N2O3:
C, 68.65; H, 8.49; N, 8.43. Found: C, 68.81; H, 8.61; N, 8.29.
General Procedure for the Preparation of 4a–c and 8
To the corresponding N-Cbz-1,2,3,4-tetrahydroisoquinoline-1-carboxamide
(2a,d, 1 mmol) or 1,2,3,4-tetrahydroisoquinoline-1-carboxamide (3a,d,e, 1 mmol),
10% aqueous HCl (10 mL) was added, and the mixture was refluxed until no more
carboxamide could be detected by TLC (20–65 h). The solvent was then evaporated
off, and the residue was purified by column chromatography, with MeOH as eluent.
6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid hydro-
chloride (4a). Yield: 169 mg (62%, starting from 2a), 197 mg (70%, starting from
2c), 205 mg (75%, starting from 3a). The physical and analytical data on 4a corre-
spond to the data in Ref. 4a.
1,2,3,4-Tetrahydroisoquinoline-1-carboxylic acid hydrochloride (4b). Yield:
160 mg (75%, starting from 2d); yield: 162 mg (76%, starting from 3d). The physical
and analytical data on 4b correspond to the data in Ref. 4a.
6,7-Diethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (4c). Yield:
108 mg (36%, starting from 3e); a white crystalline solid, mp 224–225 ꢀC; 1H (D2O): d
7.71 (1H, s, C6H2), 6.86 (1H, s, C6H2), 5.11 (1H, s, CHN), 4.09 (4H, q, J ¼ 6.5 Hz,
2 ꢁ OCH2CH3), 3.57–3.46 (2H, m, CH2N), 2.97 (2H, br s, CH2CH2N), 1.34 (6H,
t, J ¼ 6.5 Hz 2 ꢁ OCH2CH3) ppm. Anal. calcd. for C14H20ClNO4: C, 54.26; H,
6.31; Cl, 12.32, N, 4.87. Found: C, 54.09; H, 6.45; N, 4.71.
6,7-Dimethoxy-3-methyl-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid,
a 1:1 mixture of cis and trans isomers (8). Yield: 92 mg (32% starting from 7a),
1
86 mg (30% starting from 7b); a yellowish-white crystalline solid; H (D2O): d 6.95
(1H, s, C6H2), 6.87 (1H, s, C6H2), 6.61 (1H, s, C6H2), 6.59 (1H, s, C6H2), 4.62
(1H, s, CHN), 4.61 (1H, s, CHN), 3.61 (6H, s, 2 ꢁ OCH3), 3.64–3.52 (1H, m,
CH), 3.34–3.30 (1H, m, CH), 2.78–2.50 (2H, m, CH2), 1.25 (3H, d, J ¼ 6.4 Hz,
CHCH3), 1.21 (3H, d, J ¼ 6.5 Hz, CHCH3) ppm. Anal. calcd. for C13H18ClNO4:
C, 54.26; H, 6.31; Cl, 12.32, N, 4.87. Found: C, 54.09; H, 6.45; N, 4.71.

1,2,3,4-TETRAHYDROISOQUINOLINE-1-CARBOXYLIC ACID DERIVATIVES
2497
ACKNOWLEDGMENTS
The authors thank the Hungarian Scientific Research Foundation (Grant No.
OTKA K 075433) for financial support.
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