Synthesis and further transformations of 8-chloro-3,4-dihydroisoquinoline

Article abstract of DOI:10.1016/j.tet.2018.10.016

Two procedures for the synthesis of barely accessible 8-chloro-3,4-dihydroisoquinoline were investigated. The first approach is based on a directed ortho-lithiation of N-pivaloyl meta-chlorophenylethylamine, followed by formylation and subsequent ring closure under acidic conditions. In the second, more advantageous variant, the N-hydroxyethyl ortho-chlorobenzylamine intermediate undergoes a Friedel-Crafts reaction, and the resulting tetrahydro derivative is oxidized with N-bromosuccinimide. The 8-chloro-3,4-dihydroisoquinoline key intermediate is then applied in Suzuki reactions to give various 8-aryl-3,4-dihydroisoquinolines, which are finally treated with alkyl or aryllithiums to give 1-substituted 8-aryl-1,2,3,4-tetrahydroisoquinolines. These novel 1,2,3,4-tetrahydroisoquinoline derivatives can be used as building blocks in the synthesis of potential drug candidates.

Full text of DOI:10.1016/j.tet.2018.10.016

Accepted Manuscript
Synthesis and further transformations of 8-chloro-3,4-dihydroisoquinoline
Csilla Hargitai, Tamás Nagy, Judit Halász, Györgyi Koványi-Lax, Gábor Németh,
Gyula Simig, Balázs Volk
PII:
S0040-4020(18)31210-9
10.1016/j.tet.2018.10.016
TET 29849
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 August 2018
Revised Date: 8 October 2018
Accepted Date: 10 October 2018
Please cite this article as: Hargitai C, Nagy Tamá, Halász J, Koványi-Lax Gyö, Németh Gá, Simig
G, Volk Balá, Synthesis and further transformations of 8-chloro-3,4-dihydroisoquinoline, Tetrahedron
(2018), doi: https://doi.org/10.1016/j.tet.2018.10.016.
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ACCEPTED MANUSCRIPT
Graphical abstract
1

ACCEPTED MANUSCRIPT
Synthesis and further transformations of 8-chloro-3,4-dihydroisoquinoline
Csilla Hargitai, Tamás Nagy, Judit Halász, Györgyi Koványi-Lax, Gábor Németh, Gyula
Simig, Balázs Volk*
Directorate of Drug Substance Development, Egis Pharmaceuticals Plc., P.O. Box 100, H-
1475 Budapest, Hungary
* To whom correspondence should be addressed. Phone: +36 1 8035874, e-mail:
volk.balazs@egis.hu.
Abstract
Two procedures for the synthesis of barely accessible 8-chloro-3,4-dihydroisoquinoline were
investigated. The first approach is based on a directed ortho-lithiation of N-pivaloyl meta-
chlorophenylethylamine, followed by formylation and subsequent ring closure under acidic
conditions. In the second, more advantageous variant, the N-hydroxyethyl ortho-
chlorobenzylamine intermediate undergoes a Friedel-Crafts reaction, and the resulting
tetrahydro derivative is oxidized with N-bromosuccinimide. The 8-chloro-3,4-
dihydroisoquinoline key intermediate is then applied in Suzuki reactions to give various 8-
aryl-3,4-dihydroisoquinolines, which are finally treated with alkyl and aryllithiums to give 1-
substituted 8-aryl-1,2,3,4-tetrahydroisoquinolines. These novel 1,2,3,4-tetrahydroisoquinoline
derivatives can be used as building blocks in the synthesis of potential drug candidates.
Keywords
isoquinoline, lithiation, Suzuki reaction, Friedel-Crafts reaction, alkylation, cyclization
Introduction
In a recent publication [1] we presented the significant biological activity of some 1,8-
disubstituted 1,2,3,4-tetrahydroisoquinolines. As a part of the program to prepare such
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compounds we succeeded in extending Schlosser’s simple method [2] for the synthesis of 8-
methoxy-3,4-dihydroisoquinoline to the corresponding 8-fluoro compound. N-Pivaloyl-
protected 3-fluorophenylethylamine (1) was lithiated in the common ortho position of the two
aromatic substituents, and subsequently quenched with dimethylformamide to give compound
2, the acidic treatment of which led, via ring closure and in situ deprotection, to 8-fluoro-3,4-
dihydroisoquinoline (3, Scheme 1). This latter proved to be a versatile intermediate for the
synthesis of 1-alkyl(aryl)-8-amino-1,2,3,4-tetrahydroisoquinolines (5) by fluorine–amine
exchange furnishing 8-amino derivatives 4, followed by treatment with various alkyllithiums
and phenyllithium.
Scheme 1. Synthesis of 1-alkyl(aryl)-8-amino-1,2,3,4-tetrahydroisoquinolines (5)
(a) BuLi (hexane), THF, −78 °C, 2 h; (b) DMF, −78 °C → 25 °C, 1 h, 68% for the two steps; (c) aq. HCl (10%),
CH2Cl2, 25 °C, 24 h, 74%; (d) corresponding amine, 80 °C, 8−29 h, 17−51%; (e) R-Li, THF, −78 °C → 25 °C;
30 min, 63−98%.
In continuation of our studies in this field, we decided to elaborate an efficient synthesis of 8-
chloro-3,4-dihydroisoquinoline (6) that can serve as a common intermediate of novel 1,8-
disubstituted tetrahydroisoquinolines by rendering transition metal-mediated reactions
possible for the introduction of various substituents into position 8.
8-Chloro-3,4-dihydroisoquinoline (6) is mentioned in the literature only as a byproduct.
Böhme et al. prepared a mixture of 6- (7) and 8-chloro-3,4-dihydroisoquinoline (6) by
cyclization of N-(3-chlorophenethyl)formamide (8) with 33% yield (Scheme 2).[3]
Compound 6 was first characterized by Lalonde et al., who carried out the cyclization with
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oxalyl chloride via the non-isolated adduct mixture (9 and 10), and obtained, after acidic
treatment, 8-chloro-3,4-dihydroisoquinoline (6, 11% over the three steps) in addition to the
main product 6-chloro-3,4-dihydroisoquinoline (7, 65%, Scheme 2).[4]
Scheme 2. Synthetic approaches leading to the mixture of 6- (7) and 8-chloro-3,4-
dihydroisoquinoline (6)
(a) polyphosphoric acid, 140 °C, 20 min, 33% (mixture); (b) (COCl)2, CH2Cl2, 23 °C, 30 min; (c) FeCl3, −15 to
23 °C, 16 h; (d) H2SO4, MeOH, 80 °C, 16 h, 6 (11%) + 7 (65%)
Our literature survey concluded that the published synthetic routes leading to the closely
related 8-choroisoquinoline (11) are also lengthy and inefficient (Scheme 3). Pomeranz-
Fritsch cyclization of 2-chlorobenzaldahyde (12) via Schiff base results 13 in the required
product 11 with 6% yield.[5,6] Alternative approaches start from isoquinoline (14). A bromo
substituent as the blocking group was introduced into position 5 (15), the most reactive site
toward an electrophile.[7,8] The introduction of the 8-chloro substituent was performed
directly to give compound 16, that could be reduced to target compound 11.[8] As an
alternative approach, 5-bromoisoquinoloine (15) was nitrated to give 5-bromo-8-nitro
derivative 17,[7] the catalytic hydrogenation of which furnished 8-aminoisoquinoline (18).[9]
Diazotization followed by treatment with copper(I) chloride resulted in 8-chloroisoquinoline
(11).[9] Although the latter route is longer, it avoids the risk of unintended dechlorination
during the reductive removal of the 5-bromo substituent.
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Scheme 3. Targeted syntheses of 8-chloroisoquinoline (11)
(a) H2SO4, 140-150 °C, 6%; (b) Br2, AlBr3, 90-100 °C, 59%; or NBS, H2SO4, −22 to −25 °C, 79%; (c) TCCA,
H2SO4, 25 °C, 88%; (d) NaBH4, Pd/C, 2-Me-THF/MeOH, 25 °C, 44%; (e) KNO3, H2SO4; (f) H2, Pd/CaCO3,
MeCOONH4, MeOH, 10 bar, 25 °C, 53%; (g) NaNO2, HCl, 0−5 °C; (h) CuCl, HCl, 49% for the two steps.
8-Chloroisoquinoline (11) thus obtained was reduced to the tetrahydroisoquinoline 19
(Scheme 4) [5], a potential precursor of the corresponding 3,4-dihydro derivative 6. However,
Mendelson et al. described a remarkably shorter synthesis of compound 19: cyclization of
hydroxyethyl derivative 20 (easily available from 2-chlorobenzaldehyde) under Friedel-Crafts
conditions afforded the target compound 19 with 60% yield.[10] Oxidation of 1,2,3,4-
tetrahydroisoquinolines to the corresponding 3,4-dihydro derivatives is well-known in the
literature.[11]
Scheme 4. Synthetic routes leading to 8-chloro-1,2,3,4-tetrahydroisoquinoline (19), the
potential precursor of 8-chloro-3,4-dihydroisoquinoline (6)
(a) AlCl3/NH4Cl, 185 °C, 16 h, 60%; (b) H2, PtO2, MeOH, 4 bar, 25 °C, 67%.
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Results and Discussion
After surveying the literature we envisioned that the extension of Schlosser’s method would
provide the most direct approach for the synthesis of 8-chloro-3,4-dihydroisoquinoline (6). A
chloro substituent in meta position to a directed metalation group (similarly to methoxy and
fluoro moieties) is known to promote lithiation at the common ortho site.[12−17]
3-Chlorophenylethylamine (21) was converted into its pivaloyl protected congener 22 by
using pivaloyl chloride in the presence of triethylamine (Scheme 5). Surprisingly, lithiation of
N-pivaloyl-3-chlorophenylethylamine (22) with butyllithium in THF at −78 °C for 2 h
followed by treatment with dimethylformamide gave a product mixture formylated rather in
the side chain (23) than at the required ring position (24), as shown by the 1H NMR spectrum
(23 : 24 = 2.5 : 1). Acidic treatment of the crude mixture afforded the required product 6 with
9% yield. Since we could not separate the formylated products, we carried out quenching of
the lithiated intermediates with dry ice as well. A mixture of carboxylic acids 25 and 26 was
obtained in a ratio 4.5 : 1, as determined by 1H NMR after separation and characterization of
the products. Lithiation carried out in the presence of TMEDA and quenching with dry ice
resulted in an even higher ratio of side chain substituted product (25 : 26 = 8.5 : 1).
Consequently, we had to look for a more efficient route to produce our key intermediate 6.
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Scheme 5. Lithiation of N-pivaloyl-3-chlorophenylethylamine (22) with BuLi leading to
mixtures of regioisomers
(a) Me3C-COCl, Et3N, CH2Cl2, 94%; (b) BuLi (hexane), THF, −78 °C, 2 h; (c) DMF, −78 °C → 25 °C, 1 h; (d)
aq. HCl (10%), CH2Cl2, 25 °C, 24 h, 9%; (e) BuLi (hexane), THF, −78 °C, 2 h; (f) CO2, −78 °C → 25 °C, 1 h.
We decided to adopt Mendelson’s synthesis of 8-chloro-1,2,3,4-tetrahydroisoquinoline (19)
which can be simply transformed to the corresponding 3,4-dihydro derivative 6 (Scheme 6).
Unexpectedly, after heating hydroxyethyl derivative 20 with aluminum chloride and
ammonium chloride at 185 °C for 23 h, in addition to the 8-chloro- (19), a minor amount of 7-
chlorotetrahydroisoquinoline derivative (27) was identified, in a ratio of 9 : 1. Changes of the
reaction conditions (lower excess of aluminum chloride, lower reaction temperature) did not
have significant influence on the formation of the rearranged product. Aluminum catalyzed
1,2-shift of a chlorine substituent of chlorobenzenes is known in the literature.[18,19]
Although the yield of product 19 significantly decreased when compound 27 was removed by
two crystallizations of the hydrochloride salt from isopropyl alcohol, the simplicity of the
operations renders this process suitable for the production of our 3,4-dihydro key intermediate
6 by oxidation of the tetrahydro analogue 19 with N-bromosuccinimide (NBS), a widely used
method in isoquinoline chemistry.
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OH
a, b
c
O
NH
NH
NH
Cl
19
Cl
Cl
Cl
27
12
20
ratio = 9 : 1
d
e, f, g
N
NH
HCl
Cl
Cl
19 HCl
6
Scheme 6. Synthesis of 8-chloro-3,4-tetrahydroisoquinoline (6) via 8-chloro-1,2,3,4-
tetrahydroisoquinoline (19)
(a) H2N(CH2)2OH, MeOH; (b) NaBH4, 1 h, 76% for the two steps; (c) AlCl3/NH4Cl, 185 °C, 23 h, 94%; (d) salt
formation, recrystallizations, 25%; (e) NBS, K2CO3, DCM, 25 °C; (f) HCl, isopropyl acetate, toluene 65% for
the two steps; (g) DCM, aq. Na2CO3, 94%.
With compound 6 in hand, first we aimed at introducing aryl groups into position 8. Pridgen
coupled 8-chloroisoquinoline with aryl Grignard reagents in the presence of 1,3-
bis(diphenylphosphino)propane nickel(II) chloride [Ni(dppp)Cl2] catalyst in good yields.[20]
Pd-catalyzed Suzuki cross-couplings of 8-bromo-,[21−24] 8-chloro-[25] and 8-
trifluoromethanesulphonyloxy-isoquinolines[26] and 8-bromo-,[27] 8-chloro-[25] and 8-
trifluoromethanesulphonyloxy-N-protected-1,2,3,4-tetrahydroisoquinolines[23−25] with aryl
boronic acids and pinacol boronic esters are described in the literature. However, to the best
of our knowledge, similar reactions of the corresponding 8-substituted-3,4-
dihydroisoquinolines have not been reported. 8-Chloro-3,4-dihydroisoquinoline (6) underwent
effective Suzuki coupling with various arylboronic acids in the presence of
tetrakis(triphenylphoshine)palladium(0) catalyst to furnish the corresponding 8-aryl
derivatives 28 (Scheme 7).
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Scheme 7. Synthesis of 1,8-disubstituted-1,2,3,4-tetrahydroisoquinolines (29)
(a) ArB(OH)2, Pd(PPh3)4, KF, toluene, water, 95 °C; 24−30 h, 64−72%; (b) RLi, THF, −78 °C → 25 °C, 30 min,
42−67%.
Finally, 8-(4-fluorophenyl)-3,4-dihydroisoquinoline (28b) was treated with alkyllithiums and
phenyllithium
[1,28]
to
afford
1-alkyl(aryl)-8-(4-fluorophenyl)-1,2,3,4-
tetrahydroisoquinolines (29) in good yields (Scheme 7).
Conclusions
Two synthetic variants for the preparation of the hardly accessible 8-chloro-3,4-
dihydroisoquinoline are disclosed. Starting from the latter, 1-alkyl(phenyl)-8-(substituted
phenyl)-1,2,3,4-tetrahydroisoquinolines were prepared by a Suzuki reaction followed by
addition of alkyl(phenyl)lithium reagents to the C=N double bond. 8-Chloro-3,4-
dihydroisoquinoline is also an advantageous precursor of new 1,2,3,4-tetrahydroisoquinoline
building blocks.
Experimental Section
All melting points were determined on a Büchi B-540 (Flawil, Switzerland) capillary melting
point apparatus and are uncorrected. IR spectra were obtained on a Bruker ALPHA FT-IR
spectrometer (Billerica, MA, USA) in KBr pellets or as a film. The electron ionization (EI)
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mass spectra were recorded on a Clarus 560 D mass spectrometer coupled with a Clarus 500
1
13
gas chromatograph (Waltham, MA, USA). H NMR and C NMR spectra were recorded at
1
295 K on a Bruker Avance III HD 600 (Billerica, MA, USA) (600 and 150 MHz for H and
13C NMR spectra, respectively) or at ambient temperature on a Bruker Avance III 400
1
(Billerica, MA, USA) (400 and 100 MHz for H and 13C NMR spectra, respectively)
spectrometer. CDCl3 or CD3OD was used as the solvent and tetramethylsilane (TMS) as the
internal standard. Chemical shifts (δ) and coupling constants (J) are given in ppm and in Hz,
respectively. Mass spectra were recorded on a Bruker O-TOF MAXIS Impact mass
spectrometer (Billerica, MA, USA) coupled with a Dionex Ultimate 3000 RS HPLC
(Sunnyvale, CA, USA) system with a diode array detector. Exact mass values of chlorine-
35
containing compounds refer to the Cl isotope. The reactions were followed by analytical
thin-layer chromatography on silica gel 60 F254 (Darmstadt, Germany) and HPLC-MS on a
Shimadzu LC-20 HPLC equipment (Kyoto, Japan). Purifications by flash chromatography
were carried out using Merck 107736 silica gel 60 H (Darmstadt, Germany) using a hexane–
ethyl acetate, dichloromethane–methanol solvent system or methyl tert-butyl ether. All
reagents were purchased from commercial sources.
N-[2-(3-Chlorophenyl)ethyl]-2,2-dimethylpropanamide (22). Pivaloyl chloride (21.7 mL,
21.3 g, 177 mmol) in dichloromethane (40 mL) was added to a solution of 21 (22.3 mL, 25.0
g, 161 mmol) and triethylamine (26.9 mL, 19.5 g, 193 mmol) in dichloromethane (160 mL) at
0 °C. After stirring for 1 h at room temperature, the mixture was washed with an aqueous
sodium hydrogen carbonate solution (5%, 3 × 70 mL). The organic layer was dried over
MgSO4, and evaporated. The solid residue was recrystallized from heptane to afford the title
compound (35.8 g, 93%) as a white solid. Mp 61−62 °C (heptane). IR (KBr): ν = 3381, 1629,
1
1524 cm−1. H NMR (400 MHz, CDCl3): δ = 7.27−7.17 (m, 3H), 7.07 (m, 1H), 5.63 (br s,
1H), 3.48 (m, 2H), 2.80 (t, J = 6.9 Hz, 2H), 1.15 (s, 9H). 13C NMR (150 MHz, CDCl3): δ
=178.4, 141.1, 134.3, 129.8, 129.0, 127.0, 126.6, 40.4, 38.6, 35.3, 27.5. HRMS calcd. for
C13H19ClNO+ ([M+H]+): 240.1150, found: 240.1154.
8-Chloro-3,4-dihydroisoquinoline hydrochloride (6 · HCl). A solution of BuLi (1.6 M in
hexane, 17.8 mL, 28.6 mmol) was added to a solution of 22 (2.28 g, 9.52 mmol) in THF (30
mL) at −78 °C. After stirring for 2 h at −78 °C, DMF (4.4 mL, 4.2 g, 57 mmol) was added.
The mixture was stirred for 2 h. After warming to ambient temperature, the reaction mixture
was diluted with a saturated aqueous solution of ammonium chloride (15 mL), and extracted
with ethyl acetate (15 and 2 × 10 mL). The combined organic layer was washed with brine
(10 mL), dried over MgSO4, and evaporated. The residue was dissolved in dichloromethane
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(25 mL) and aqueous hydrochloric acid (15%, 60 mL) and the mixture was vigorously stirred
for 24 h at 25 °C. The aqueous layer was washed with diethyl ether (35 mL), and the organic
layer was extracted with water (15 mL). The combined aqueous layers were evaporated, and
the residue was recrystallized from ethanol/diethyl ether to afford the title compound (173
mg, 9%) as a pale yellow solid. Mp 175−177 °C (ethanol/diethyl ether, off-white solid). IR
(KBr): ν = 3444, 1671 cm−1. 1H NMR (600 MHz, CDCl3): δ = 9.18 (br s, 1H), 7.68 (dd, J =
8.0, 7.6 Hz, 1H), 7.52 (br d, J = 8.0 Hz, 1H), 7.31 (br d, J = 7.6 Hz, 1H), 4.05 (m, 2H), 3.19
13
(br t, J = 8.2 Hz, 2H). C NMR (150 MHz, CDCl3): δ = 161.5, 139.5, 139.1, 138.6, 130.0,
127.2, 122.1, 41.0, 24.9. HRMS calcd. for C9H9ClN+ ([M+H]+): 166.0418, found: 166.0418.
2-(3-Chlorophenyl)-3-(2,2-dimethylpropanamido)propanoic acid (25) and 2-chloro-6-[2-
(2,2-dimethylpropanamido)ethyl]benzoic acid (26). A solution of BuLi (1.6 M in hexane,
37.5 mL, 60.0 mmol) was added to a solution of 22 (4.79 g, 20.0 mmol) in THF (60 mL) at
−78 °C. After stirring for 2 h at −78 °C, the mixture was poured into dry ice. After the
reaction was complete the mixture was diluted with water (50 mL). The layers were
separated, and the organic layer was extracted with water (15 mL). The combined aqueous
layer was washed with diethyl ether (30 mL), and acidified with hydrochloric acid. The
aqueous layer was extracted with dichloromethane (3 × 40 mL). The organic layer was dried
over MgSO4. The solvent was evaporated, the residue was triturated in hexane, and filtered.
The pale brown solid was recrystallized from ethyl acetate to afford the title compound (25,
1.55 g, 27%) as a white solid. Mp 164−165 °C (ethyl acetate). IR (KBr): ν = 3419, 1702,
1620, 1531 cm−1. 1H NMR (600 MHz, CDCl3): δ = 7.31−7.26 (m, 3H), 7.18 (m, 1H), 6.15 (br
t, J = 6.0 Hz, 1H), 3.97 (dd, J = 8.5, 6.1 Hz, 1H), 3.69 (m, 1H), 3.62 (m, 1H), 1.13 (s, 9H). 13C
NMR (150 MHz, CDCl3): δ = 179.4, 175.7, 137.8, 134.7, 130.1, 128.2, 128.1, 126.4, 50.2,
+
42.1, 38.7, 27.3. HRMS calcd. for C14H19ClNO3 ([M+H]+): 284.1048, found: 284.1054.
The filtrate was purified by flash chromatography (100% methyl tert-butyl ether) to afford the
title compound (26, 0.22 g, 4%) as a white solid. Mp 160−162 °C (methyl tert-butyl ether). IR
(KBr): ν = 3420, 1708, 1614, 1535 cm−1. 1H NMR (600 MHz, CDCl3): δ = 7.29 (dd, J = 8.1,
1.2 Hz, 1H), 7.26 (dd, J = 8.1, 7.4 Hz, 1H), 7.12 (br dd, J = 7.4, 1.2 Hz, 1H), 6.37 (br t, J =
13
5.7 Hz, 1H), 3.58 (m, 2H), 2.92 (t, J = 7.1 Hz, 2H), 1.07 (s, 9H). C NMR (150 MHz,
CDCl3): δ = 180.3, 169.3, 136.9, 134.9, 130.4, 130.0, 128.6, 127.8, 40.4, 38.6, 22.4, 27.3.
+
HRMS calcd. for C14H19ClNO3 ([M+H]+): 284.1048, found: 284.1050.
2-(3-Chlorophenyl)-3-(2,2-dimethylpropanamido)propanoic acid (25) and 2-chloro-6-[2-
(2,2-dimethylpropanamido)ethyl]benzoic acid (26). 22 (2.40 g, 10.02 mmol) in THF (30
mL) was added to a solution of TMEDA (4.5 mL, 3.5 g, 30 mmol) and BuLi (1.6 M in
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hexane, 18.8 mL, 30.0 mmol) at −78 °C. After stirring for 2 h at −78 °C, the mixture was
poured onto dry ice. After the reaction was complete the mixture was diluted with water (25
mL). The layers were separated, and the organic layer was extracted with water (25 mL). The
combined aqueous layer was washed with diethyl ether (15 mL), and acidified with
hydrochloric acid. The aqueous layer was extracted with dichloromethane (3 × 20 mL). The
organic layer was dried over MgSO4. The solvent was evaporated, the residue was triturated
in hexane, and filtered. The pale brown solid was recrystallized from ethyl acetate to afford
the title compound (25, 0.64 g, 23%) as a white solid. Mp 164−165 °C (ethyl acetate). The
filtrate was purified by flash chromatography (100% methyl tert-butyl ether) to afford the title
compound (26, 51 mg, 2%) as a white solid. Mp 160−162 °C (methyl tert-butyl ether).
8-Chloro-1,2,3,4-tetrahydroisoquinoline hydrochloride (19 · HCl). To the mixture of 20
(10.00 g, 45.05 mmol) and ammonium chloride (1.76 g, 32.9 mmol) aluminum chloride
(11.60 g, 87.02 mmol) was added at 185 °C. After 40 min and 70 min further portions of
aluminum chloride (5.80 g, 43.5 mmol and 11.60 g, 87.02 mmol) were added and the mixture
was stirred for further 23 h at the same temperature. It was poured into a slurry of ice and 3 M
HCl solution under strong agitation. The resulting solution was basified (pH 14) with 40%
NaOH and extracted with diethyl ether (300 mL and 2 × 150 mL). The organic layer was
dried (MgSO4), and evaporated resulting in an oily residue (7.07 g, 94%) containing the two
isomers 19 and 27 in a ratio of 9 : 1 as determined by GC-MS. It was dissolved in isopropyl
alcohol (50 mL) and a solution of hydrochloric acid gas in isopropyl alcohol was added
dropwise. The precipitate was filtered off. The residue was recrystallized twice from
isopropyl alcohol to afford the title compound (2.32 g, 25%) as a pale brown solid. Mp
244−246 °C (isopropyl alcohol, off-white solid). IR (KBr): ν = 3423, 1587, 1468 cm−1. 1H
NMR (400 MHz, CD3OD): δ = 7.37 (br d, J = 7.7 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.24 (br
d, J = 7.7 Hz, 1H), 4.37 (s, 2H), 3.49 (t, J = 6.3 Hz, 2H), 3.14 (br t, J = 6.3 Hz, 2H). 13C NMR
(100 MHz, CD3OD): δ = 135.6, 133.3, 130.2, 129.0, 128.8, 127.3, 43.9, 42.2, 26.2. HRMS
calcd. for C9H11ClN+ ([M+H]+): 168.0575, found: 168.0580.
A small amount of the primary oily product mixture obtained above was separated by flash
chromatography to give 8- and 7-chloro-1,2,3,4-tetrahydroisoquinoline (19 and 27).
8-Chloro-1,2,3,4-tetrahydroisoquinoline (19). 1H NMR (600MHz, CD3OD): 7.17 (d, J = 7.7
Hz, 1H), 7.10 (t, J = 7.7 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1H), 3.92 (br s, 2H), 3.01 (t, J = 6.0 Hz,
2H), 2.81 (t, J = 6.0 Hz, 2H).
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1
7-Chloro-1,2,3,4-tetrahydroisoquinoline (27). H NMR (600MHz, CD3OD): 7.20 (dd, J =
8.2, 2.3 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 4.12 (s, 2H), 3.27 (t, J =
6.2 Hz, 2H), 2.93 (br t, J = 6.2 Hz, 2H).
7-Chloro-1,2,3,4-tetrahydroisoquinoline hydrochloride (27 · HCl). The corresponding
hydrochloride salt was prepared by addition of a solution of hydrochloric acid gas in
isopropyl acetate to the solution of the base (27) in toluene followed by filtration. IR (film): ν
1
= 3483, 1591, 1486 cm−1. H NMR (600MHz, CD3OD): 7.30 (dd, J = 8.1, 2.2 Hz, 1H), 7.29
(br s, 1H), 7.25 (d, J = 8.1 Hz, 1H), 4.35 (br s, 2H), 3.50 (t, J = 6.4 Hz, 2H), 3.10 (br t, J = 6.4
13
Hz, 2H). C NMR (150MHz, CD3OD): 133.7, 131.8, 131.5, 131.3, 129.3, 127.7, 45.4, 42.7,
25.6. HRMS calcd. for C9H11ClN+ ([M+H]+): 168.0575, found: 168.0578.
8-Chloro-3,4-dihydroisoquinoline hydrochloride (6 · HCl). To a suspension of 19 · HCl
(5.57 g, 27.3 mmol) and potassium carbonate (4.90 g, 35.5 mmol) in dichloromethane (100
mL) N-bromosuccinimide (9.72 g, 54.6 mmol) was added portionwise over 15 min. After
stirring for 30 min at room temperature 30% aqueous sodium hydroxide solution (50 mL) and
water (50 mL) were added, and the mixture was stirred for 15 min. The layers were separated,
and the aqueous layer was extracted with diethyl ether (2 × 40 mL). The combined organic
layer was washed with water (20 mL), dried over MgSO4, and evaporated. The residue was
triturated in diethyl ether and filtered. The filtrate was evaporated, dissolved in toluene (35
mL) and a solution of hydrochloric acid gas in isopropyl acetate was added dropwise. The
precipitate was filtered off and recrystallized from ethanol/diethyl ether to afford the title
compound (3.57 g, 65%) as a pale yellow solid. Mp 175–177 °C (ethanol/diethyl ether, off-
white solid). Spectral data are identical with those of the product obtained using the lithiation
process.
8-Chloro-3,4-dihydroisoquinoline (6). To a vigorously stirred mixture of 6 · HCl (6.25 g,
30.9 mmol) in dichloromethane (100 mL) and water (50 mL) aqueous sodium carbonate
(10%, 20 mL) was added. The layers were separated and the aqueous layer was extracted with
dichloromethane (3 × 25 mL). The combined organic layer was washed with water (2 × 50
mL) and brine (50 mL) and dried over MgSO4. The solvent was evaporated to afford the title
1
compound (4.82 g, 94%) as a yellow oil. IR (film): ν = 1620 cm−1. H NMR (400 MHz,
CDCl3): δ = 8.82 (t, J = 2.2 Hz, 1H), 7.27 (m, 2H), 7.07 (m, 1H), 3.76 (m, 2H), 2.73 (br m,
2H). 13C NMR (150 MHz, CDCl3): δ = 156.5, 139.0, 133.3, 131.7, 128.2, 126.0, 125.2, 46.8,
25.2.
General procedure for the synthesis of compounds 28a–f. A mixture of 6, 4-
methylphenylboronic
acid
(1.3
eq),
12
potassium
fluoride
(3
eq),

ACCEPTED MANUSCRIPT
tetrakis(triphenylphosphine)palladium(0) (0.015 eq) in toluene and water was heated to 95 °C
for 24 h (28a−d) or 30 h (28e,f) in a sealed tube. Upon cooling, the layers were separated and
the aqueous layer was extracted with diethyl ether. The combined organic layer was washed
with brine, and dried over MgSO4. The solvents were evaporated, the residue was purified by
flash chromatography (5−50% ethyl acetate in hexane). The corresponding hydrochloride salt
was prepared by addition of a solution of hydrochloric acid gas in isopropyl acetate to the
solution of the base in toluene followed by filtration.
8-(4-Methylphenyl)-3,4-dihydroisoquinoline hydrochloride (28a). This compound was
prepared according to general procedure using 6 (501 mg, 3.03 mmol), 4-
methylphenylboronic acid (535 mg, 3.93 mmol), potassium fluoride (527 mg, 9.09 mmol),
tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.045 mmol) in toluene (8 mL) and water (2
mL). The title compound (530 mg, 68%) was isolated as a pale brown solid. Mp 228−230 °C
(isopropyl alcohol/diethyl ether, off-white solid). IR (KBr): ν = 2479, 1670, 1519 cm−1. 1H
NMR (600 MHz, CD3OD): δ = 8.48 (br m, 1H), 7.85 (t, J = 7.7 Hz, 1H), 7.57 (m, 1H), 7.51
(m, 1H), 7.39 (m, 2H), 7.34 (d, J = 8.2 Hz, 2H), 4.03 (m, 2H), 3.30 (br t, J = 7.9 Hz, 2H), 2.44
13
(s, 3H). C NMR (100 MHz, CD3OD): δ = 166.8, 149.1, 140.7, 140.4, 138.7, 135.1, 131.3,
130.8, 130.7, 128.5, 123.4, 42.2, 26.2, 21.3. HRMS calcd. for C16H16N+ ([M+H]+): 222.1277,
found: 222.1303.
8-(4-Fluorophenyl)-3,4-dihydroisoquinoline hydrochloride (28b). This compound was
prepared according to general procedure using 6 (2.01 g, 12.2 mmol), 4-fluorobenzeneboronic
acid (2.21 g, 15.8 mmol), potassium fluoride (2.11 g, 36.4 mmol),
tetrakis(triphenylphosphine)palladium(0) (283 mg, 0.182 mmol) in toluene (30 mL) and water
(5 mL). The title compound (2.29 g, 72%) was isolated as a pale brown solid. Mp 224−225 °C
(isopropyl alcohol/diethyl ether, off-white solid). IR (KBr): ν = 2475, 1668, 1512 cm−1. 1H
NMR (400 MHz, CD3OD): δ = 8.73 (br s, 1H), 7.87 (t, JHH = 7.7 Hz, 1H), 7.58 (br d, JHH
=
7.7 Hz, 1H), 7.54 (br d, JHH = 7.7 Hz, 1H), 7.50 (dd, JHH = 8.8 Hz, JHF = 5.3 Hz, 2H), 7.31 (t,
13
JHH = JHF = 8.8 Hz, 2H), 4.03 (m, 2H), 3.31 (br m, 2H). C NMR (150 MHz, CD3OD): δ =
166.9, 164.9 (d, JCF = 248 Hz), 147.8, 140.5, 138.8, 134.3 (d, JCF = 3.3 Hz), 133.4 (d, JCF
=
8.7 Hz), 130.9, 128.9, 123.6, 117.0 (d, JCF = 22.0 Hz), 42.2, 26.2. HRMS calcd. for
C15H13FN+ ([M+H]+): 226.1026, found: 226.1046.
8-(4-Methoxyphenyl)-3,4-dihydroisoquinoline hydrochloride (28c). This compound was
prepared according to general procedure using 6 (500 mg, 3.02 mmol), 4-
methoxyphenylboronic acid (597 mg, 3.93 mmol), potassium fluoride (526 mg, 9.07 mmol),
tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.045 mmol) in toluene (8 mL) and water (2
13

ACCEPTED MANUSCRIPT
mL). The title compound (572 mg, 69%) was isolated as a pale brown solid. Mp 217−219 °C
(isopropyl alcohol/diethyl ether, off-white solid). IR (KBr): ν = 2461, 1667, 1515 cm−1. 1H
NMR (400 MHz, CD3OD): δ = 8.72 (br s, 1H), 7.84 (t, J = 7.7 Hz, 1H), 7.56 (br d, J = 7.7 Hz,
1H), 7.49 (br d, J = 7.7 Hz, 1H), 7.39 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H), 4.03 (m,
13
2H), 3.88 (s, 3H), 3.30 (br t, J = 7.9 Hz, 2H). C NMR (100 MHz, CD3OD): δ = 166.9,
162.3, 148.9, 140.5, 138.7, 132.7, 130.7, 130.2, 128.2, 123.4, 115.6, 56.0, 42.1, 23.3. HRMS
calcd. for C16H16NO+ ([M+H]+): 238.1226, found: 238.1234.
Methyl 4-(3,4-dihydroisoquinolin-8-yl)benzoate hydrochloride (28d). This compound was
prepared according to general procedure using 6 (502 mg, 3.03 mmol), 4-
methoxycarbonylphenylboronic acid (710 mg, 3.94 mmol), potassium fluoride (528 mg, 9.10
mmol), tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.045 mmol) in toluene (8 mL) and
water (2 mL). The title compound (648 mg, 71%) was isolated as a pale brown solid. Mp
229−231 °C (isopropyl alcohol/diethyl ether, off-white solid). IR (KBr): ν = 2488, 1734, 1589
cm−1. 1H NMR (400 MHz, CD3OD): δ = 8.74 (br s, 1H), 8.20 (d, J = 8.4 Hz, 2H), 7.90 (t, J =
7.7 Hz, 1H), 7.62 (br d, J = 7.7 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.58 (br d, J = 7.7 Hz, 1H),
13
4.05 (m, 2H), 3.32 (br t, J = 7.9 Hz, 2H). C NMR (150 MHz, CD3OD): δ = 167.9, 166,7,
147.5, 142.7, 140.6, 138.8, 131.9, 131.6, 131.0, 130.8, 129.5, 123.5, 52.9, 42.3, 26.1. HRMS
+
calcd. for C17H16NO2 ([M+H]+): 266.1176, found: 266.1178.
8-(3,4-Dimethoxyphenyl)-3,4-dihydroisoquinoline hydrochloride (28e). This compound
was prepared according to general procedure using 6 (503 mg, 3.04 mmol), 3,4-
dimethoxyphenylboronic acid (719 mg, 3.95 mmol), potassium fluoride (529 mg, 9.12 mmol),
tetrakis(triphenylphosphine)palladium(0) (71 mg, 0.046 mmol) in toluene (8 mL) and water (2
mL). The title compound (617 mg, 67%) was isolated as a yellow solid. Mp 197−199 °C
(isopropyl alcohol/diethyl ether). IR (KBr): ν = 1659, 1515, 1255 cm−1. 1H NMR (400MHz,
CD3OD): 8.75 (br s, 1H), 7.84 (t, J = 7.7 Hz, 1H), 7.60 (br d, J = 7.7 Hz, 1H), 7.49 (br d, J =
7.7 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.95 (dd, J = 8.2, 2.0 Hz, 1H),
13
4.03 (br t, J = 7.9 Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.29 (m, 2H). C NMR (150MHz,
CD3OD): 166.9, 151.7, 150.8, 148.9, 140.4, 138.6, 130.70, 130.69, 128.3, 124.8, 123.5, 114.5,
+
112.9, 56.7, 56.5, 42.1, 26.3. HRMS calcd. for C17H18NO2 ([M+H]+): 268.1332, found:
268.1339.
8-(2H-1,3-Benzodioxol-5-yl)-3,4-dihydroisoquinoline hydrochloride (28f). This compound
was prepared according to general procedure using 6 (500 mg, 3.02 mmol), 3,4-
methylenedioxyphenylboronic acid (652 mg, 3.93 mmol), potassium fluoride (526 mg, 9.07
mmol), tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.045 mmol) in toluene (8 mL) and
14

ACCEPTED MANUSCRIPT
water (2 mL). The title compound (556 mg, 64%) was isolated as a yellow solid. Mp 198−200
1
°C (isopropyl alcohol/diethyl ether). IR (KBr): ν = 1645, 1469, 1255 cm−1. H NMR
(600MHz, CD3OD): 8.76 (br s, 1H), 7.83 (t, J = 7.7 Hz, 1H), 7.55 (br d, J = 7.7 Hz, 1H), 7.50
(br d, J = 7.7 Hz, 1H), 7.01 (d, J = 1.8 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.87 (dd, J =8.0, 1.8
Hz, 1H), 6.06 (s, 2H), 4.05 (m, 2H), 3.29 (t, J = 8.0 Hz, 2H). 13C NMR (150 MHz, CD3OD):
166.8, 150.3, 149.9, 148.7, 140.4, 138.7, 131.9, 130.7, 128.4, 126.0, 123.5, 111.1, 109.6,
+
103.2, 42.1, 26.3. HRMS calcd. for C16H14NO2 ([M+H]+): 252.1025, found: 252.1029.
8-(4-Fluorophenyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (29a). A
solution of MeLi (1.6 M in hexane, 1.9 mL, 3.1 mmol) was added to a suspension of 28b (403
mg, 1.54 mmol) in THF (15 mL) at −78 °C. The mixture was stirred for 30 min at room
temperature. The reaction mixture was diluted with a saturated aqueous solution of
ammonium chloride (4 mL) and water (4 mL). The layers were separated and the aqueous
layer was extracted with diethyl ether (2 × 8 mL). The combined organic layer was dried over
MgSO4. The solvents were evaporated, the residue was purified by flash chromatography
(1−6% methanol in dichloromethane). The corresponding hydrochloride salt was prepared by
addition of a solution of hydrochloric acid gas in isopropyl acetate to the solution of the base
in toluene followed by filtration and recrystallization from isopropyl alcohol/diethyl ether to
afford the title compound (181 mg, 42%) as a white solid. Mp 255−257 °C (isopropyl
alcohol/diethyl ether). IR (KBr): ν = 2958, 1606 cm−1. 1H NMR (400 MHz, CD3OD): δ =
7.38−7.32 (m, 3H), 7.28 (br d, JHH = 7.7 Hz, 1H), 7.23 (t, JHH = JHF = 8.8 Hz, 2H), 7.11 (br d,
JHH = 7.4 Hz, 1H), 4.80 (q, JHH = 6.9 Hz, 1H), 3.56 (m, 1H), 3.46 (m, 1H), 3.20 (m, 2H), 1.22
13
(d, JHH = 6.9 Hz, 3H). C NMR (150 MHz, CD3OD): δ = 163.9 (d, JCF = 246 Hz), 141.2,
137.5 (d, JCF = 3.6 Hz), 132.5, 132.3, 132.0 (d, JCF = 8.1 Hz), 130.6, 130.1, 129.1, 116.7 (d,
JCF = 21.7 Hz), 50.0, 37.4, 26.2, 18.7. HRMS calcd. for C16H17FN+ ([M+H]+): 242.1345,
found: 242.1366.
1-Butyl-8-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (29b).
A
solution of BuLi (1.6 M in hexane, 1.9 mL, 3.1 mmol) was added to a suspension of 28b (400
mg, 1.53 mmol) in THF (15 mL) at −78 °C. The mixture was stirred for 30 min at room
temperature. The reaction mixture was diluted with a saturated aqueous solution of
ammonium chloride (4 mL) and water (4 mL). The layers were separated and the aqueous
layer was extracted with diethyl ether (2 × 8 mL). The combined organic layer was dried over
MgSO4. The solvents were evaporated, the residue was purified by flash chromatography
(1−5% methanol in dichloromethane). The corresponding hydrochloride salt was prepared by
addition of a solution of hydrochloric acid gas in isopropyl acetate to the solution of the base
15

ACCEPTED MANUSCRIPT
in toluene followed by filtration. The title compound (327 mg, 67%) was isolated as a white
solid. Mp 204−206 °C (isopropyl alcohol/diethyl ether). IR (KBr): ν = 2961, 1604 cm−1. 1H
NMR (400 MHz, CD3OD): δ = 7.39−7.34 (m, 3H), 7.28 (br d, JHH = 7.8 Hz, 1H), 7.23 (t, JHH
= JHF = 8.8 Hz, 2H), 7.14 (m, 1H), 4.71 (dd, JHH = 9.7, 3.8 Hz, 1H), 3.56 (m, 1H), 3.43 (m,
1H), 3.21 (m, 2H), 1.68 (m, 1H), 1.53 (m, 1H), 1.22 (m, 1H), 1.14− 0.86 (m, 3H), 0.71 (t, JHH
= 7.2 Hz, 3H). 13C NMR (100 MHz, CD3OD): 163.8 (d, J = 246 Hz), 141.3, 137.6 (d, J = 3.6
Hz), 133.2, 132.2 (d, J = 8.3 Hz), 131.9, 130.6, 129.9, 129.1, 116.7 (d, J = 21.9 Hz), 54.3,
38.2, 33.5, 28.7, 26.2, 22.7, 13.8. HRMS calcd. for C19H23FN+ ([M+H]+): 284.1815, found:
284.1814.
8-(4-Fluorophenyl)-1-hexyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (29c).
A
solution of hexyllithium (2.5 M in hexane, 1.2 mL, 3.1 mmol) was added to a suspension of
28b (402 mg, 1.54 mmol) in THF (15 mL) at −78 °C. The mixture was stirred for 30 min at
room temperature. The reaction mixture was diluted with a saturated aqueous solution of
ammonium chloride (4 mL) and water (4 mL). The layers were separated and the aqueous
layer was extracted with diethyl ether (2 × 8 mL). The combined organic layer was dried over
MgSO4. The solvents were evaporated, the residue was purified by flash chromatography
(1−2% methanol in dichloromethane). The corresponding hydrochloride salt was prepared by
addition of a solution of hydrochloric acid gas in isopropyl acetate to the solution of the base
in toluene followed by filtration. The title compound (276 mg, 52%) was isolated as a white
solid. Mp 179−181 °C (isopropyl alcohol/diethyl ether). IR (KBr): ν = 2927, 1601 cm−1. 1H
NMR (400 MHz, CD3OD): δ = 7.36 (m, 3H), 7.28 (br d, JHH = 7.7 Hz, 1H), 7.24 (t, JHH = JHF
= 8.8 Hz, 2H), 7.14 (br d, JHH = 7.5 Hz, 1H), 4.71 (dd, JHH = 9.7, 3.7 Hz, 1H), 3.56 (m, 1H),
3.43 (m, 1H), 3.21 (m, 2H), 1.68 (m, 1H), 1.51 (m, 1H), 1.20 (m, 1H), 1.17 (m, 2H),
13
1.10−0.89 (m, 5H), 0.84 (t, JHH = 7.2 Hz, 3H). C NMR (150 MHz, CD3OD): 163.8 (d, J =
246 Hz), 141.3, 137.6 (d, J = 3.6 Hz), 133.2, 132.2 (d, J = 7.9 Hz), 131.9, 130.6, 129.9, 129.1,
116.8 (d, J = 21.8 Hz), 54.2, 38.2, 33.7, 32.3, 29.2, 26.5, 26.2, 23.5, 14.3. HRMS calcd. for
C21H27FN+ ([M+H]+): 312.2128, found: 321.2122.
8-(4-Fluorophenyl)-1-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (29d). A
solution of PhLi (1.9 M in dibutyl ether, 1.6 mL, 3 mmol) was added to a suspension of 28b
(401 mg, 1.53 mmol) in THF (15 mL) at −78 °C. The mixture was stirred for 30 min at room
temperature. The reaction mixture was diluted with a saturated aqueous solution of
ammonium chloride (4 mL) and water (4 mL). The layers were separated and the aqueous
layer was extracted with diethyl ether (2 × 8 mL). The combined organic layer was dried over
MgSO4. The solvents were evaporated, the residue was purified by flash chromatography
16

ACCEPTED MANUSCRIPT
(0−2% methanol in dichloromethane). The corresponding hydrochloride salt was prepared by
addition of a solution of hydrochloric acid gas in isopropyl acetate to the solution of the base
in toluene followed by filtration. The title compound (278 mg, 53%) was isolated as a white
solid. Mp 248−250 °C (isopropyl alcohol/diethyl ether). IR (KBr): ν = 2952, 1601 cm−1. 1H
NMR (400 MHz, CD3OD): δ = 7.45 (m, 1H), 7.41 (dd, JHH = 7.9, 1.7 Hz, 1H), 7.33 (m, 1H),
7.27 (m, 2H), 7.09 (dd, JHH = 7.1, 1.7 Hz, 1H), 6.93-6.77 (m, 6H), 5.76 (s, 1H), 3.44−3.28 (m,
4H). 13C NMR (150 MHz, CD3OD): δ = 163.4 (d, JCF = 245 Hz), 142.4, 137.2, 137.1 (d, JCF =
3.3 Hz), 133.8, 131.8 (d, JCF = 8.3 Hz), 131.0, 130.48, 130.46, 129.9, 129.8, 129.6, 115.9 (d,
JCF = 21.7 Hz), 48.1, 38.0, 26.3. HRMS calcd. for C21H19FN+ ([M+H]+): 304.1502, found:
304.1514.
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