A Unified Synthesis of Bifunctional 4-Substituted-1,2,3,4-tetrahydroisoquinoline Derivatives

Article abstract of DOI:10.1081/SCC-120027247

Starting from a single, commercially available bromoisoquinoline, convenient (multigram) syntheses of 4-substituted-1,2,3, 4-tetrahydroisoquinoline derivatives have been developed. The compounds thus prepared show suitable substitution patterns for further derivatization and constitute a new family of compounds of potential pharmacological interest.

Full text of DOI:10.1081/SCC-120027247

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A Unified Synthesis of Bifunctional
4‐Substituted‐1,2,3,4‐tetrahydroisoquinoline
Derivatives
M. Carmen Bernabeu a , José Luis Díaz a , Oscar Jiménez a & Rodolfo Lavilla a b
a Parc Científic de Barcelona , Josep Samitier, 1‐5, 08028, Barcelona, Spain
b Laboratory of Organic Chemistry, Faculty of Pharmacy , University of Barcelona ,
Barcelona, Spain
Published online: 16 Aug 2006.
To cite this article: M. Carmen Bernabeu , José Luis Díaz , Oscar Jiménez & Rodolfo Lavilla (2004) A Unified Synthesis of
Bifunctional 4‐Substituted‐1,2,3,4‐tetrahydroisoquinoline Derivatives, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 34:1, 137-149, DOI: 10.1081/SCC-120027247
To link to this article: http://dx.doi.org/10.1081/SCC-120027247
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 1, pp. 137–149, 2004
A Unified Synthesis of Bifunctional
4-Substituted-1,2,3,4-tetrahydroisoquinoline
Derivatives
1
M. Carmen Bernabeu, Jose Luis Dıaz, Oscar Jimenez,
1
1
´
´
´
and Rodolfo Lavilla1,2,
*
1
´
Parc Cientıfic de Barcelona, Barcelona, Spain
2Laboratory of Organic Chemistry, Faculty of Pharmacy,
University of Barcelona, Barcelona, Spain
ABSTRACT
Starting from a single, commercially available bromoisoquinoline,
convenient (multigram) syntheses of 4-substituted-1,2,3,4-tetrahydroiso-
quinoline derivatives have been developed. The compounds thus prepared
show suitable substitution patterns for further derivatization and
constitute a new family of compounds of potential pharmacological
interest.
Key Words: Nucleophilic aromatic substitutions; Protecting groups;
Combinatorial chemistry; Copper; Hydrogenation.
*
´
Correspondence: Rodolfo Lavilla, Parc Cientıfic de Barcelona, Josep Samitier, 1–5,
08028, Barcelona, Spain; Fax: þ34-934037225; E-mail: rlavilla@pcb.ub.es.
137
DOI: 10.1081/SCC-120027247
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

138
Bernabeu et al.
INTRODUCTION
One promising source of new and biologically relevant compounds
resides in the development of original (or unexplored) substitution patterns
among the so-called privileged structures.[1–4] In this context, although
tetrahydroisoquinolines can be regarded as the key subunits in many bio-
active compounds,[5–9] this scaffold still offers opportunities for further
development.
Tetrahydroisoquinolines bearing suitable substituents at position 4 (thus
displaying two functional points for diversification) could provide new
chemical entities (NCEs) which may evolve into selective drugs. In the course
of a research project, we became interested in these heterocyclic systems, and
needed a practical access to such structures.
Some of these compounds have previously been prepared by different
methods. However, many of these syntheses involve long sequences, use a
broad range of starting materials and routes (and therefore are not connected),
and/or are scarcely described in the literature. The present paper deals with
the development of a divergent synthesis for a family of these compounds
(tetrahydroisoquinoline derivatives 2–4) from a single commercially
available isoquinoline in a short and flexible (amenable for diversification)
protocol. The retrosynthetic analysis (Sch. 1) basically involves the
introduction of the substituent at position 4 through a formal SNAr, the
reduction of the pyridine ring moiety and the subsequent functional group
transformations (including optional protection steps).
Scheme 1. Retrosynthetic analysis of compounds 2–4.

Synthesis of Bifunctional Derivatives
RESULTS AND DISCUSSION
139
Initially we decided to explore the synthesis of 4-hydroxy-1,2,3,4-
tetrahydroisoquino-line (2a) from 4-bromoisoquinoline 1 as depicted in Sch.
2. It should be noted that the preparation of this compound has been previously
described in the literature from phthalaldehyde and from 2-carboxybenzalde-
hyde through a 3–4 step synthetic sequences.[10–13]
The bromomoisoquinoline 1 was treated with sodium hydroxide in the
presence of copper at high temperature, affording the hydroxyisoquinoline 5,
as described in the literature.[14–16]
Alternatively, this compound could also be prepared by diazotization of
aminoisoquinoline 7 (see below) in 89% yield.[17] Esterification of 5 was
carried out according to a known procedure to yield acetate 6.[18] The catalytic
hydrogenation of acetate 6 (PtO2, AcOH) afforded a mixture of the expected
4-acetoxy-tetrahydroisoquinoline together with the corresponding 4-hydroxy-
N-acetamide derivative (probably the result of a spontaneous O to N acyl
transfer). The crude mixture was subsequently subjected to basic hydrolysis to
give the desired tetrahydroisoquinoline 2a in 69% yield. This aminoalcohol
was selectively N-Boc protected, using standard conditions, to afford
hydroxyurethane 2b in almost quantitative yield. The conversion of the
protected alcohol 2b into the amino derivative 3d through displacement
reactions or an oxidation-reductive amination sequence was tried without
success.
The 4-amino(amido) derivatives 3 were obtained from 4-bromoisoquino-
line 1 following an analogous procedure: the amination of 1 (autoclave,
aqueous ammonia, CuSO4) was performed using a modification of the
reported procedure[19] provided the aminoisoquinoline 7 in an improved 98%
yield. Treatment of 7 with equimolecular amounts of the corresponding
anhydride furnished amides 8a–c, in excellent yields (method A).
More conveniently, compounds 8a (41%) and 8b (83%) have been
synthesized directly from 4-bromoisoquinoline 1 by N-arylation with
acetamide or benzamide respectively (method B), using a modified version
of the recently described Buchwald procedure (Sch. 3).[20]
Finally, 4-acylamino-1,2,3,4-tetrahydroisoquinolines 3a–c were pre-
pared by catalytic hydrogenation of the corresponding amides.[21] However, in
this reaction, the isomeric 5,6,7,8-tetrahydro derivatives [for instance, 11a
(16%), 11b (2%)], resulting from the reduction of the benzene ring, were also
produced (Fig. 1). Interestingly, as in the previous series, no hydrogenolytic
interference was detected. It should be noted that the attachment of an
electron-withdrawing group upon the substituent at position 4 seems to be a
requisite for the selective (although not exclusive) reduction of the pyridine
ring moiety on 4-hydroxy- and 4-aminoisoquinolines.[22] The basic hydrolysis

140
Bernabeu et al.
Scheme 2. Reagents and conditions: (a) NaOH, CuSO4, Cu (bronze) 2108C (60%);
(b) Ac2O reflux (71%); (c) H2 (1 atm), PtO2, AcOH, rt (71–88%); (d) 3M KOH, reflux
(69%); (e) (Boc)2O, Et3N, CH2Cl2 (99%); (f) NH3(aq), CuSO4, 1708C (98%); (g)
(RCO)2O, pyr,1008C (92–99%); (h) 3M KOH, reflux (99%); (i) CuCN, 2258C (81%);
(j) MeOH, H2SO4, reflux (70%); (k) H2O reflux (90%).

Synthesis of Bifunctional Derivatives
141
Scheme 3. Reagents and conditions: a) CuI, K3PO4, polyethylenimine, acetamide or
benzamide. 8a, dioxane, reflux (41%); 8b, toluene, reflux (83%).
of benzamide 3b gave the desired 4-amino-1,2,3,4-tetrahydroisoquinoline 3d
in quantitative yield.
The 1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (4b) and its methyl
ester 4a were prepared according to a similar procedure. 4-Bromoisoquinoline
was cleanly transformed into nitrile 9 (CuCN, 2258C) in excellent yield.[23]
The alcoholysis of 9 using standard conditions (MeOH–H2SO4) proceeded in
70% yield to afford the corresponding methyl ester 10 and the catalytic
hydrogenation of this compound using PtO2 in AcOH yielded the tetrahydro
derivative 4a. The hydrolysis of the ester function with neat water (probably
through an internal general base catalysis) gave the pure b-amino acid 4b in
90% yield.
EXPERIMENTAL
Melting points were determined in a capillary tube and are uncorrected.
TLC was done on Merck silica gel coated plates (60 F254). Flash
chromatography was carried out on Merck silica gel (60 A CC, 35–70 mm).
Figure 1. Compounds 11a and 11b.

142
Bernabeu et al.
IR spectra were recorded on a Nicolet 205 FT-IR spectrophotometer. NMR
spectra were measured with Varian Gemini-200 (200 MHz) and Varian
Gemini-300 (300 MHz) spectrometers. Mass spectra were recorded in the
electron impact (EI) mode on a Hewlett-Packard model 5898A. Elemental
analyses were performed on a Carlo Erba Instrument EA-1108 in the Serveis
´ `
Cientıfico-Tecnics de la Universitat de Barcelona.
4-Hydroxyisoquinoline (5). A mixture of 4-bromoisoquinoline (10.5 g,
50.5 mmol), hydrated CuSO4 (5 g), copper bronze (4.1 g) and NaOH (31.3 g,
757.5 mmol) in water (17 mL) was heated in an autoclave at 2108C for 12 h.
After cooling to room temperature, the dark brown residue was extracted with
hot water, and carbon dioxide gas was bubbled through the aqueous extract to
precipitate the 4-hydroxyisoquinoline 5 (4.4 g, 60%); mp 223–2258C (EtOH)
(lit.[14] 2238C). 1H-NMR (200 MHz, DMSO-d6): d ¼ 7.64 (1H, m), 7.70 (1H,
m), 8.02 (1H, d, J 8.4), 8.04 (1H, s), 8.10 (1H, d, J 8.0), 8.78 (1H, s) and 10.35
(1H, br s).
4-Acetoxyisoquinoline (6). A mixture of hydroxy derivative 5 (900 mg,
6.16 mmol) and 10 mL of acetic anhydride was stirred at reflux temperature
for 5 h. After cooling to room temperature, the solution was concentrated
under reduced pressure and the residue was taken up in EtOAc (50 mL), made
alkaline (pH ¼ 8) with saturated aqueous NaHCO3 solution, the organic layer
was separated and the aqueous phase was extracted with AcOEt (3 Â 35 mL).
The combined organic layers were dried (Na2CO3–Na2SO4), filtered and
concentrated to afford crude 6 (818 mg, 71%) as a light-yellow oil, which
1
solidified on standing, mp 52–548C (hexanes), (lit.[24] 54–558C). H-NMR
(200 MHz, CDCl3): d ¼ 2.49 (3H, s), 7.66 (1H, m), 7.75 (1H, m), 7.85 (1H, d,
J 8.4), 8.03 (1H, d, J 8.0), 8.40 (1H, s) and 9.17 (1H, s).
1,2,3,4-Tetrahydro-4-hydroxyisoquinoline (2a). PtO2 (25 mg) was
added to a solution of 4-acetoxyisoquinoline (6, 250 mg, 1.34 mmol) in
AcOH (25 mL), the resulting suspension was hydrogenated (1 atm) at room
temperature. After completion of the reaction (TLC control) the catalyst was
removed by filtration throught a short pad of celite and the filtrates were
concentrated under reduced pressue to afford an oily residue (182 mg, 71%).
The residue was taken up in an aqueous solution of KOH (3M, 30 mL) and
refluxed for 24 h. The mixture was then diluted with brine and throughly
extracted with EtOAc (6 Â 20 mL). After drying (K2CO3) the solvent was
evaporated to give essentially pure aminoalcohol 2a (138 mg, 69%) as a red
viscous oil. IR (film): 3292, 2922, 1449, 1030 and 744 cm21 1H-NMR
.
(200 MHz, CDCl3): d ¼ 2.94 (1H, dd, J 13.1 and 3.0 Hz), 3.12 (1H, dd, J 13.1
and 3.0 Hz), 3.29 (2H, br s), 3.78 (2H, d, J 4.8 Hz), 4.48 (1H, t, J 3.0 Hz), 6.96
(1H, m), 7.20 (2H, m), 7.34 (1H, m).
N-tert-butyloxycarbonyl-4-hydroxy-1,2,3,4-tetrahydroisoquino-
line (2b). A solution of 1,2,3,4-tetrahydro-4-hydroxyisoquinoline 2a (89 mg,

Synthesis of Bifunctional Derivatives
143
0.60 mmol) in dry CH2Cl2 (6 mL) was stirred at 08C under nitrogen
atmosphere. Di-tert-butyl-dicarbonate (143 mg, 0.65 mmol) and Et3N (90 mL,
0.65 mmol) were then added to the solution, and the resulting mixture was
stirred for 4 h at room temperature. The solvent was removed under reduced
pressure and the residue was taken up in EtOAc (10 mL) and washed with
saturated aqueous NaHCO3 solution and brine. The organic layer was dried
over Na2SO4, filtered, and concentrated to yield 2b (148 mg, 99%) as yellow
oil. IR (film): 3420, 1682, 1417, 1164, 887 and 748 cm21 1H-NMR
.
(200 MHz, CDCl3): d ¼ 1.47 (9H, s), 3.61 (1H, dd, J 13.3 and 3.8 Hz), 3.81
(1H, dd, J 13.3 and 5.4 Hz), 4.44 (1H, d, J 17.0 Hz), 4.71 (2H, m), 7.11 (1H,
m), 7.25 (2H, m) and 7.46 (1H, m). 13C-NMR (50.3 MHz, CDCl3): d ¼ 28.5,
45.6, 48.0, 66.0, 80.3, 125.8, 126.8, 127.7, 128.0, 133.1, 136.7 and 155.2. MS
(EI): m/z ¼ 249 (Mþ, 28) 192 (43), 148 (27), 146 (20), 130 (41), 119 (12), 118
(15), 91 (12) and 57 (100). HRMS: m/z calcd for C14H19NO3: 249.1365;
found: 249.1378.
4-Aminoisoquinoline (7). A mixture of 4-bromoisoquinoline (10.44 g,
49.2 mmol), concentrated NH4OH solution (30%, 120 mL) and hydrated
CuSO4 (5 g) were heated for 24 h at 165–1708C in an autoclave. The reaction
mixture was cooled to room temperature, diluted with an aqueous NaOH
(20%, 200 mL) solution and extracted with EtOAc (5 Â 200 mL). The organic
layer were dried (Na2SO4), filtered, treated with decolorizing charcoal, filtered
and concentrated under reduced pressure to afford pure aminoisoquinoline 7
1
(7.0 g, 98%); mp 108–1108C (Et2O) (lit.[19] 108.58C). H-NMR (200 MHz,
CDCl3): d ¼ 4.10 (2H, m), 7.59–7.75 (2H, m), 7.79 (1H, m), 7.91 (1H, m),
8.05 (1H, s) and 8.75 (1H, s). 13C-NMR (50.3 MHz, CDCl3): d ¼ 120.1,
126.0, 127.1, 127.8, 128.0, 128.6, 129.0, 137.0 and 143.0 MS (EI): m/z ¼ 145
(Mþ þ 1, 11%), 144 (100), 117 (44), 116 (14), 90 (28), 89 (24).
4-Acetamidoisoquinoline (8a). Method A:
A solution of acetic
anhydride (5.2 mmol) in pyridine (1 mL) was added dropwise to a stirred
solution of compound 7 (5.2 mmol) in pyridine (5 mL). The reaction mixture
was stirred at 1008C under nitrogen atmosphere, and after completion of the
reaction (monitored by TLC, reaction time 45 min), it was quenched with
saturated aqueous NaHCO3 solution and the resulting mixture was throughly
extracted with CHCl3 (5 Â 20 mL). The organic extracts were dried (Na2CO3
–Na2SO4), filtered, and concentrated under reduced pressure to yield
essentially pure amide 8a (93%). An analytically pure sample was obtained
through chromatography on silica gel (EtOAc/MeOH/Et3N 90 : 10 : 2); mp
168–1698C (Hexane/EtOAc) (lit[19] 167–1688C). 1H-NMR (300 MHz,
CDCl3): d ¼ 2.33 (3H s), 7.58–7.76 (2H, m), 7.84 (1H, d, J 8.4 Hz), 8.00
(1H, d, J 8.0 Hz), 8.35 (1H, br s), 8.68 (1H, s) and 9.01 (1H, s). Method B: To a
resealable Schlenk tube, or alternatively a screw-cap test tube, were added CuI
(10 mol%), acetamide (1.2 mmol) and K3PO4 (2.1 mmol), and the reaction

144
Bernabeu et al.
vessel was fitted with a rubber septum. The vessel was evacuated and
back-filled with argon. 4-Bromoisoquinoline (1.0 mmol), polyethylenimine
(20 mg), and dioxane (1 mL) were then successively added under a stream of
argon. The reaction tube was quickly sealed and the contents were stirred
while heating in an oil bath at 1008C until the reaction was finished (10 days).
The reaction mixture was cooled to ambient temperature, diluted with EtOAc
(2–3 mL), and filtered through a plug of silica gel, eluting with additional
EtOAc (10–20 mL). The filtrate was concentrated and the resulting residue
was purified by column chromatography to provide the desired product 8a
(41%).
4-Benzamidoisoquinoline (8b). Following the method A from 4-
bromoisoquinoline and benzoic anhydride (reaction time 1 h 30 min), amide
8b (92%) was obtained; mp 189–1908C (Hexane/EtOAc) (lit.[19] 188–
1
1898C). H-NMR (200 MHz, CDCl3): d ¼ 7.47–7.77 (5H, m), 7.88 (1H, d,
J 7.6 Hz), 7.99 (3H, m), 8.40 (1H, s), 8.87 (1H, s) and 9.12 (1H, s). 13C-NMR
(50.3 MHz, CDCl3): d ¼ 120.8, 127.3, 127.4, 128.0, 128.1, 128.8, 130.7,
130.9, 132.2, 134.0, 139.1, 149.7, 150.6 and 166.5. Following the method B,
from 4-bromoisoquinoline and benzamide in toluene at 1108C (reaction time 6
days), amide 8b (83%) was obtained.
4-Trifluoroacetamidoisoquinoline (8c). Following the method
A
with trifluoroacetic anhydride (reaction time 20 min), amide 8c (99%)
1
was obtained as a viscous oil. H-NMR (200 MHz, CDCl3): d ¼ 7.70–7.84
(3H, m), 8.07 (1H, d, J 8.0 Hz), 8.65 (1H, br s), 8.82 (1H, s) and 9.22 (1H, s).
MS (EI): m/z ¼ 241 (Mþ þ 1, 13%), 240 (Mþ, 100%), 145 (17), 128 (27),
117 (14) and 116 (95). HRMS: m/z calcd for C11H7F3N2O: 240.0519; found:
240.0510.
General procedure for the preparation of 4-amido-1,2,3,4-tetrahy-
droisoquinoline derivatives (3a–c). A suspension of 4-acylaminoisoquino-
line 8 (1.0 mmol) in AcOH (20 mL) and PtO2 (20 mg) was hydrogenated
(1 atm) at room temperature. After completion of the reaction (monitored by
TLC), the catalyst was removed by filtration through a short pad of celite and
the filtrates were concentrated under reduced pressure. The residue was taken
up in CHCl3, basified (pH ¼ 8–9) with an aqueous saturated NaHCO3
solution, the organic layer was separated and the aqueous phase was extracted
with CHCl3 (3 Â 30 mL). The combined organic layers were dried with
(K2CO3), filtered, and concentrated to afford the crude product. Purification by
flash chromatography gave the desired 1,2,3,4-tetrahydroisoquinoline
derivative 3.
4-Acetamido-1,2,3,4-tetrahydroisoquinoline (3a). (73%); mp 124–
1258C (MeOH/Et2O) (lit.[21] 124–126.58C). IR (film): 3276, 3025, 2929,
1
1649, 1547 and 1289 cm21. H-NMR (200 MHz, CDCl3): d ¼ 1.92 (3H, s),
2.41 (1H, s), 3.02 (1H, dd, J 12.6 and 3.6 Hz), 3.10 (1H, dd, J 12.6 and 3.5 Hz),

Synthesis of Bifunctional Derivatives
145
3.77 (1H, d, J 16.0 Hz), 3.90 (1H, d, J 16.0 Hz), 4.97 (1H, m) and 6.94–7.31
(5H, m). 13C-NMR (50.3 MHz, CDCl3): d ¼ 23.2, 45.9, 47.9, 49.3, 126.2,
126.6, 127.3, 129.4, 134.9, 135.7 and 169.3. MS (EI): m/z ¼ 191 (Mþ þ 1,
2%), 132 (11), 131 (97), 130 (100), 119 (43), 118 (42) and 117 (22).
4-Acetamido-5,6,7,8-tetrahydroisoquinoline (11a). This compound
was isolated (16%) in the hydrogenation of 4-acetamidoisoquinoline 8a, mp
120–1228C (Et2O) (lit.[21] 118–120.58C). 1H-NMR (200 MHz, CDCl3):
d ¼ 1.78 (4H, m), 2.19 (3H, s), 2.59 (2H, m), 2.74 (2H, m), 7.85 (1H, br s),
8.12 (1H, s) and 8.51 (1H, s). MS (EI): m/z ¼ 190 (Mþ, 52), 149 (11), 148
(100), 147 (64), 133 (21) and 132 (12).
4-Benzamido-1,2,3,4-tetrahydroisoquinoline (3b). (87%); mp 138–
1
1398C (Et2O) (lit.[21] 138.5–1408C). H-NMR (200 MHz, CDCl3): d ¼ 2.25
(1H, br s), 3.18 (2H, m), 3.97 (2H, m), 5.25 (1H, m), 7.00–7.49 (8H, m)
and 7.74 (2H, d, J 7.6 Hz). 13C-NMR (50.3 MHz, CDCl3): d ¼ 46.4, 48.2,
49.6, 126.2, 126.8, 127.0, 127.5, 128.4, 129.6, 131.4, 134.4, 135.0, 135.9,
166.4. MS (EI): m/z ¼ 252 (Mþ, 1%), 132 (10), 131 (100), 130 (79) and
105 (87).
4-Trifluoroacetamido-1,2,3,4-tetrahydroisoquinoline (3c). (83%);
1
m.p. 119–1208C. IR (film): 3322, 1700, 1215 and 1184 cm21. H-NMR
(200 MHz, CDCl3): d ¼ 2.84 (1H, br s), 3.15 (1H, dd, J 12.4 and 2.9 Hz), 3.25
(1H, dd, J 12.4 and 2.4 Hz) 3.88 (1H, d, J 15.6 Hz), 4. 00 (1H, d, J 15.6 Hz),
5.13 (1H, m), 7.08 (1H, m), 7.21–7.39 (3 H, m) and 7.64 (1H, m). 13C-NMR
(50.3 MHz, CDCl3): d ¼ 46.6, 47.5, 48.7, 116.0 (q, JC-F 287), 126.8, 127.1,
128.1, 129.6, 132.9, 135.1 and 156.3 (q, JC-F 35 Hz). MS (EI): m/z ¼ 244
(Mþ, 2%), 146 (54), 132 (15), 131 (100), 130 (87) and 118 (46). Anal. Calcd
for C11H11F3N2O: C, 54.10; H, 4.54; N, 11.47. Found: C, 54.15; H, 4.72; N,
11.49.
4-Amino-1,2,3,4-tetrahydroisoquinoline (3d). A suspension of benza-
mide 3b (77 mg, 0.31 mmol) in a 3M aqueous KOH solution (20 mL) was
stirred at reflux temperature for 5 h. The resulting mixture was then diluted
with brine and extracted thoroughly with CHCl3 (6 Â 25 mL). The organic
extracts were dried (K2CO3), filtered and concentrated under reduced pressure
1
to yield pure 3d (99%). IR (film) 3329, 3214 and 1651 cm21. H-NMR
(200 MHz, CDCl3): d ¼ 1.78 (3 H, br s), 2.96 (1H, dd, J 12.8 and 4.4 Hz), 3.15
(1H, dd, J 12.8 and 3.9 Hz), 3.88 (1H, m), 3.99 (2H, m) and 6.99–7.36 (4H,
m). 13C-NMR (50.3 MHz, CDCl3): d ¼ 48.0, 48.5, 52.1, 126.0, 126.5, 126.8,
128.6, 135.7 and 139.1. MS (EI): m/z ¼ 149 (Mþ þ 1, 4%), 148 (Mþ, 25),
131 (63%), 130 (29) and 119 (100). HRMS: m/z calcd for C9H12N2: 148.1000.
Found 148.1009.
4-Cyanoisoquinoline (9). 4-Bromoisoquinoline (1, 5.10 g, 24.3 mmol)
was mixed thoroughly with CuCN (7.6 g, 84.9 mmol). The powdered mixture
was heated at 2258C for 45 min. After cooling to room temperature, the

146
Bernabeu et al.
mixture was dissolved in a saturated aqueous NaHCO3 solution (100 mL). A
concentrated aqueous NH4OH solution (15 mL) was added and the resulting
mixture was stirred vigorously overnight, then it was extracted with EtOAc
(3 Â 200 mL). The combined organic layers were washed with brine, dried
(Na2SO4), filtered and concentrated under reduce pressure to give nitrile 9
(3.4 g, 81%); mp 105–1068C (Hexane/Et2O) (lit.[22] 1048C). 1H-NMR
(200 MHz, CDCl3): d ¼ 7.81 (1 H, m), 7.95 (1 H, m), 8.12 (1 H, d, J 8.0 Hz),
8.20 (1 H, d, J 8.0 Hz), 8.92 (1 H, s) and 9.44 (1 H, s).
Methyl 4-isoquinolinecarboxylate (10). Concd. H2SO4 (2 mL) was
added to a solution of nitrile 9 (256 mg, 1.66 mmol) in MeOH (7 mL). The
mixture was stirred at reflux temperature for 48 h. After completion of the
reaction (monitored by GC-HPLC), the solvent was removed under reduced
pressure, and the residue was taken up in EtOAc (25 mL), cooled to 08C and
made alkaline (pH ¼ 8) with a saturated aqueous NaHCO3 solution. The
phases were separated and the aqueous layer was extracted with AcOEt
(3 Â 25 mL). The combined organic layers were dried (Na2CO3–Na2SO4),
filtered and concentrated to afford ester 10 (216 mg, 70%). mp 82–838C
1
(lit.[22] 818C). H-NMR (200 MHz, CDCl3): d ¼ 4.04 (3H, s), 7.69 (1H, m),
7.85 (1H, m), 8.04 (1H, d, J 8.4), 8.95 (1H, d, J 9.1), 9.19 (1H, s) and 9.38 (1H,
s). 13C-NMR (50.3 MHz, CDCl3): d ¼ 52.4, 120.4, 125.0, 127.6, 127.8, 128.2,
132.2, 133.8, 146.7, 156.9, 166.8.MS (EI): m/z ¼ 188 (Mþ þ 1, 10%), 187
(Mþ, 80%), 156 (100%) and 128 (97).
Methyl 1,2,3,4-tetrahydroisoquinoline-4-carboxylate (4a). Following
the general procedure for the hydrogenation of isoquinoline derivatives,
(reaction time 24 h), the reduced ester 4a (139 mg, 88%) was obtained in
essentially pure form as a yellow oil and was used without further purification
in the next step. 1H-NMR (200 MHz, CDCl3): d ¼ 2.27 (1H, br s), 3.08 (1H,
dd, J13.6 and 4.8Hz), 3.47 (1H, d, J 13.6 Hz), 3.63 (1H, m), 3.68 (3H, s), 3.98
(2H, m) and 7.00–7.26 (4H, m).
1,2,3,4-Tetrahydroisoquinoline-4-carboxylic acid (4b). A suspension
of aminoester 4a (405 mg, 2.12 mmol) in water (10 mL) was stirred at reflux
temperature for 24 h. The mixture was cooled to room temperature and then
was washed with Et2O (3 Â 25 mL). The aqueous phase was evaporated to
dryness to afford aminoacid 4b as a white solid (338 mg, 90%); mp. 237–
1
2388C. IR (film): 3063, 3016, 1584 and 1390 cm21. H-NMR (200 MHz,
D2O): d ¼ 3.24 (1 H, dd, J 12.4 and 4.4 Hz), 3.53 (1H, dd, J 12.4 and 3.9 Hz),
3.68 (1H, m), 4.20 (2H, m) and 7.02–7.26 (4H, m). 13C-NMR (50.3 MHz,
D2O): d ¼ 41.2, 41.8, 41.9, 124.6, 125.1, 125.5, 125.9, 126.3, 128.8 and
176.9. MS (EI): m/z ¼ 179 (Mþ þ 2, 1%), 178 (Mþ þ 1, 5%), 177 (Mþ,
42%), 176 (47), 160 (12), 148 (12), 132 (37), 131 (48) and 130 (100). Anal.
Calcd for C10H11NO2: C, 67.78; H, 6.28; N, 7.90. Found: C, 67.63; H, 6.42; N,
7.73.

Synthesis of Bifunctional Derivatives
CONCLUSIONS
147
A unified synthesis for several 4-substitued-1,2,3,4-tetrahydroisoquino-
lines has been developed, involving the use of a single starting material (a
commercially available isoquinoline) in a fast (3–4 steps), flexible and
practical (multigram) protocol. The key reactions involved are the copper-
promoted SNAr and the catalytic hydrogenation upon the 4-substituted
isoquinolines to furnish the synthetic targets 2, 3 and 4 in good yields.
Although the prepared compounds are racemates, their resolution (if
convenient or desirable at a later stage) may be routinely addressed by chiral
HPLC or derivatization (being amines or carboxylic acids).
ACKNOWLEDGMENTS
Financial support from the DGICYT, Spain (project BQU2000-0235) is
´ ´
gratefully acknowledged. Drs Dolors Fernandez and Juan Miguel Jimenez
(Almirall Prodesfarma, Barcelona) are thanked for useful suggestions.
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Received in Poland July 7, 2003