Synthetic approaches to 1-(2-chlorophenyl)isoquinoline-3-carboxylic acid

Article abstract of DOI:10.1039/b110301f

In connection with our research of new antitumor compounds, previously undescribed approaches to the 1-(2-chlorophenyl)isoquinoline-3-carboxylic acid 9 are reported here. Two related accesses from phenylethylamine or amphetamine were investigated and were found to be successful. A more robust synthesis, using Suzuki's cross-coupling between 2-chlorophenylboronic acid 15 and the previously unreported methyl-1-bromoisoquinoline-3-carboxylate 14 was also developed. This synthetic route provides the ground for a combinatorial approach to the core structure of new potential peripheral benzodiazepine receptor ligands.

Full text of DOI:10.1039/b110301f

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Synthetic approaches to 1-(2-chlorophenyl)isoquinoline-
3-carboxylic acid
Yves L. Janin,*a Emmanuel Roulland,a Arnaud Beurdeley-Thomas,b Didier Decaudin,b
Claude Monnereta and Marie-France Pouponb
1
a UMR 176 CNRS-Institut Curie, 26 rue d’Ulm, 75231 Paris cedex 05, France
b UMR 147 CNRS-Institut Curie, 26 rue d’Ulm, 75231 Paris cedex 05, France
Received (in Cambridge, UK) 12th November 2001, Accepted 8th January 2002
First published as an Advance Article on the web 22nd January 2002
In connection with our research of new antitumor compounds, previously undescribed approaches to the
1-(2-chlorophenyl)isoquinoline-3-carboxylic acid 9 are reported here. Two related accesses from phenylethylamine
or amphetamine were investigated and were found to be successful. A more robust synthesis, using Suzuki’s
cross-coupling between 2-chlorophenylboronic acid 15 and the previously unreported methyl-1-bromoisoquinoline-
3-carboxylate 14 was also developed. This synthetic route provides the ground for a combinatorial approach to the
core structure of new potential peripheral benzodiazepine receptor ligands.
Introduction of a cyanide moiety on position 3 of compound
Introduction
6a was attempted using known procedures: either with diethyl-
cyanophosphonate10 or trimethylsilyl cyanide.11 No cyanation
took place whereas a slow reduction of the N-oxide 6a into 5a
was observed in both types of trial. Such a reduction has
already been reported in the cases of nitropyridine N-oxide12
and 1-methylisoquinoline-2-oxide.10
In connection with our interest1–4 in peripheral benzodiazepine
receptor ligands such as PK 11195 15,6 and Ro 5-4864 2
(Fig. 1) we have investigated the synthesis of the 1-(2-chloro-
Two methods of methyl oxidation were applied on 5b. (a) The
radical-based bromination13 (or chlorination) of 5b resulted in
a very low yield of the polyhalogenated derivative along with
extensive decomposition. (b) A much more efficient preparation
of the aldehyde 7 from 5b (97% yield) was achieved with
selenium oxide in boiling 1,2-dichlorobenzene (iv on Scheme 1).
Fig. 1 Structures of PK 11195 and Ro 5-4864.
phenyl)isoquinoline structure of 1. No preparation of this
structure has yet been published7 and therefore we wish to
report here our contribution to the chemistry of functionalised
isoquinolines.
Results and discussion
We began this work with two related approaches starting with
phenylethylamine or amphetamine.† From these two amines,
ortho-chlorobenzamides 3a, b were prepared and the iso-
quinoline nucleus was formed using phosphorus oxychloride in
boiling acetonitrile. Surprisingly, if dihydroisoquinoline 4a was
obtained in 72% yield, its methyl homologue 4b was only
obtained in 37% yield along with 2-chlorobenzonitrile resulting
from a fragmentation reaction (i.e. a retro-Ritter reaction8).
Aromatization of 4a into 5a was achieved in only 25% yield
using sulfur in boiling decalin,‡ but in 72% yield when an excess
of manganese oxide was repeatedly added in boiling benzene
over a four day period. On the other hand, a 65% yield of
5b was obtained using sulfur in boiling decalin9 whereas no
compound could be isolated in the course of trials with dichloro-
dicyanoquinone in boiling dioxane. The corresponding N-
oxides 6a, b were obtained using 3-chloroperoxybenzoic acid
in dichloromethane.
Scheme 1 i: POCl3–MeCN, reflux. ii S8–decalin, reflux or MnO2–
benzene, reflux. iii: MCPBA–CH2Cl2. iv: SeO2, 180 ЊC. v: (CF3CO)2O,
180 ЊC. vi: AgNO3, NaOH–EtOH–H2O 1 : 1.
† The IUPAC name for amphetamine is α-methylphenethylamine.
‡ The IUPAC name for decalin is decahydronaphthalene.
DOI: 10.1039/b110301f
J. Chem. Soc., Perkin Trans. 1, 2002, 529–532
This journal is © The Royal Society of Chemistry 2002
529

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It is noteworthy that very little oxidation was observed with
selenium oxide in boiling dioxane and none if manganese oxide
was used instead.
2-chlorophenol 17 (resulting from a concurrent oxidative
dehydroboration22,23) and of a small amount of a mixture of
unidentified polyaryl compounds.24 On the other hand, the
coupling reaction of compound 15 (using only 3 mol% of
tetrakis(triphenylphosphine)palladium) with the brominated
derivative 14 led to the ester 16 in 90% isolated yield, if 2
equivalents of arylboronic acid 15 and potassium phosphate
were added in two portions over 16 hours. It is noteworthy that
a complete ester hydrolysis has been reported if the palladium-
catalysed coupling of compound 13 and 1-naphthylboronic
derivative is made in the presence of potassium carbonate in
DME.16 In our case we had to proceed to a subsequent basic
hydrolysis of the ester 16 to obtain the target acid 9 in 95%
yield.
Another previously unreported method developed here, is
based on the known rearrangement of 2-alkylpyridine N-
oxides.14 Boiling N-oxide 6b with an excess of trifluoroacetic
anhydride in 1,2-dichlorobenzene, followed by hydrolysis, gave
the alcohol 8 in 68% yield. In contrast to pyridine chemistry,15
no reaction took place in dichloromethane and little in boiling
acetonitrile. This last method does provide an alternative to the
use of toxic selenium oxide which is often detrimental to bio-
logical studies. Further oxidation of aldehyde 7 (or alcohol
8), into the target acid 9 was then achieved using silver nitrate
under basic conditions.13
The final approach was investigated independently from a
recently published work.16 We started from the readily avail-
able 17 dihydroisoquinoline carboxylic acid 10. Its esterification
into 11,18 followed by an aromatization using palladium over
charcoal in boiling diphenyl ether, provided an access to the
isoquinolinone 12 in 67% overall yield (Scheme 2). Another
Conclusion
This work indicates that, compared to pyridine, isoquinoline
chemistry benefits from quite drastic heating increase for
(i) the selenium oxide oxidation of compound 5b or (ii)
the rearrangement of N-oxide 6b. Our preparation of the
1-chloroisoquinoline derivatives 13 and, more crucially the
1-bromoisoquinoline 14, allowed the study of the Suzuki
palladium-catalysed aryl cross-coupling reaction. Starting from
compound 14, this remarkable reaction proceeds with 90%
yield, without any ester hydrolysis, and thus provides a new
efficient access to 1-phenylisoquinolines such as 9. This last
synthetic route will hopefully lead to a combinatorial approach
in the preparation of new potential peripheral benzodiazepine
receptor ligands.
Experimental
General
1H and 13C NMR spectra were recorded on a Bruker Avance-
300 spectrometer. Unless otherwise stated, CDCl3 was the sol-
vent used. Shifts are given in ppm (δ) with respect to the TMS
signal and coupling constants (J) are given in Hertz. Low and
high resolution mass spectra were obtained by Mrs Nicole
Morin (Ecole Normale Supérieure, 24 rue Lhomond F-75231
Paris) on a MS 700 JEOL using methane as the ionization
vector. Column chromatography was performed on Merck
silica gel 60/35–70 µm. Solvents were usually dried using
activated25 3 Å or 4 Å molecular sieve.
Amides 3a, b
Scheme 2 i: MeOH, H2SO4, reflux. ii Pd/C, (C6H5)2O, 259 ЊC. iii:
POX3, K2CO3–MeCN, reflux. iv: K3PO4, Pd(PPh3)4–DMF, 80 ЊC.
Phenylethylamine or amphetamine (28.5 mmol) and 2-
chlorobenzoyl chloride (5 g, 28.5 mmol) in dry acetonitrile
(100 ml) were cooled to 0 ЊC. Dry triethylamine (4.4 ml,
31.4 mmol) was added and the suspension was allowed to warm
up for 2 hours. This mixture was concentrated to dryness, dis-
persed in dichloromethane, washed with water and the organic
phase was dried over magnesium sulfate prior to concentration
to dryness. The oily residues obtained were in both cases used in
the next step without further purification.
16
preparation of 12 was recently published and an even more
direct approach to 12 has also been reported.19 The use of
phosphorus oxychloride to prepare compound 12 was some-
time fraught with side reactions. Although a very efficient
procedure has been recently reported,16 we developed a robust
method, also using phosphorus oxychloride or bromide, but
in the presence of potassium carbonate in boiling acetonitrile.
Thus the troublesome hydrolysis of the reaction mixture takes
place under neutral conditions, without heat evolution, and
avoids unwanted decomposition. The 1-halogenated derivatives
13 or 14 were thus routinely prepared in 82–85% yields.
Suzuki20,21 coupling reaction trials in DMF using potassium
phosphate and 2-chlorophenylboronic acid 15 showed that
yields, starting with the chlorinated derivative 13, were never
better than 50% and that the separation of 13 and ester 16 was
quite difficult. This result is very similar to the 50% yield
reported for the cross-coupling of compound 13 and a hindered
1-naphthylboronic derivative.16 Moreover, side reactions and
catalyst deactivation took place when additions of arylboronic
acid 15 and potassium phosphate were repeated. Analysis of
the reaction mixture showed the formation of some volatile
2-Chloro-N-phenylethylbenzamide 3a. νmax (KBr)/cmϪ1 3273,
2337, 1786, 1641, 1555; 1H: 2.99 (t, 2H, J = 7.0, CH2), 3.79 (m,
2H, CH2), 6.21 (m, 1H, NH), 7.21–7.39 (m, 8H), 7.64 (m, 1H);
13C: 32.3, 41.1, 126.4, 126.8, 128.5, 128.7, 129.7, 130.0, 130.5,
131.0, 135.0, 138.6, 165.5; m/z 260.0837 (Mϩ ϩ H, C15H14NOCl
requires 260.0842).
N-(2-Chlorobenzoyl)amphetamide 3b. νmax (KBr)/cmϪ1 3290,
3029, 2968, 1641, 1536; 1H: 1.22 (d, 3H, J = 6.6, CH3), 2.86 (m,
2H, CH2), 4.46 (s, 1H, NH), 7.29 (m, 8H), 7.54 (m, 1H); 13C:
19.8, 42.3, 47.0, 126.4, 126.9, 128.3, 129.4, 130.0, 130.5, 131.0,
133.3, 137.7, 165.8; m/z 274.0996 (Mϩ ϩ H, C16H17NOCl
requires 274.0998).
530
J. Chem. Soc., Perkin Trans. 1, 2002, 529–532

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3,4-Dihydroisoquinolines 4a, b
graphed over silica gel (dichloromethane–ethanol 97 : 3) to give
the N-oxides 6a, b.
The crude product 3a or 3b (78 mmol) and phosphorus oxy-
chloride (22 ml, 235 mmol) were refluxed in dry acetonitrile
(300 ml) for 3 hours. The solution was cautiously poured on
600 ml of cold water. The resulting mixture was stirred for one
hour. The solution was made basic with sodium hydroxide
pellets and stirred while cooling. This was extracted with
dichloromethane, the organic phase was washed with water,
dried over magnesium sulfate and concentrated to dryness. The
crude residue was chromatographed over silica gel eluting with
dichloromethane–ethanol 99 : 1 in the case of 4a or heptane–
ethyl acetate 7 : 3 in the case of 4b.
1-(2-Chlorophenyl)isoquinoline N-oxide 6a. Obtained as a
1
wax (82%). νmax (KBr)/cmϪ1 3327, 2361, 1324, 1223; H: 7.31–
7.56 (m, 7H), 7.66 (d, 1H, J = 7.2), 7.76 (d, 1H, J = 8.5), 8.23 (d,
1H, J = 7.2); 13C: 123.7, 124.6, 126.8, 127.1, 128.2, 128.6, 129.2,
129.9 (2 signals ?), 130.3, 130.7, 131.2, 134.3, 137.0, 143.9;
m/z 240.0573 (Mϩ ϩ H Ϫ O, C15H11NCl requires 240.0580, the
molecular peak was too small for an HRMS).
1-(2-Chlorophenyl)-3-methylisoquinoline
N-oxide
6b.
Obtained as an oil (88%). νmax (KBr)/cmϪ1 3056, 2922, 1360,
1334, 1295; 1H: 2.57 (m, 3H, CH3), 7.11 (d, 1H, J = 8.8), 7.25–
7.50 (m, 5H), 7.61 (s, 1H), 7.62 (d, 1H, J = 9.2); 13C: 18.4, 123.4,
124.8, 126.6, 127.7, 128.6, 129.1, 130.3, 131.0, 131.7, 131.8,
134.8, 144.5, 146.4; m/z 270.0690 (Mϩ ϩ H, C16H12NOCl
requires 270.0686).
1-(2-Chlorophenyl)-3,4-dihydroisoquinoline 4a. This com-
pound was obtained in 72% yield (from phenylethylamine) as
1
a wax. νmax (KBr)/cmϪ1 3186, 2897, 2847, 2661, 1615; H: 2.79
(m, 4H, CH2), 6.83 (d, 1H, J = 7.5), 7.14 (m, 2H), 7.30 (m, 5H);
13C: 26.3, 48.1, 127.36, 127.37, 127.9, 129.3, 130.0, 130.3, 130.5,
130.8, 131.4, 133.0, 137.6, 138.6, 166.7; m/z 242.0746 (Mϩ ϩ H,
C15H13NCl requires 242.0737).
1-(2-Chlorophenyl)isoquinoline-3-carboxaldehyde 7
Compound 5b (1.15 g, 4.42 mmol) and selenium oxide (1.62 g,
13.2 mmol) were refluxed in 1,2-dichlorobenzene for 6 hours.
The suspension was concentrated to dryness, dispersed in
dichloromethane and filtered. The filtrate was concentrated
again and the residue chromatographed over silica gel (heptane–
ethyl acetate 2 : 8) to give the aldehyde 7 (1.15 g, 97%) as a solid
which was used without further purification. νmax (KBr)/cmϪ1
3357, 2843, 2363, 1707; 1H: 7.45 (m, 3H), 7.54 (m, 1H), 7.68 (m,
2H), 7.78 (m, 1H), 8.07 (d, 1H, J = 8.1), 8.44 (s, 1H, H-4), 10.24
(s, 1H, CHO); 13C: 121.5, 127.5, 127.9, 129.5, 129.8, 130.4,
130.6, 130.7, 131.6, 131.63, 133.7, 136.2, 137.9, 146.5, 160.1,
194.0; m/z 268.0541 (Mϩ ϩ H, C16H11NOCl requires 268.0529).
1-(2-Chlorophenyl)-3-methyl-3,4-dihydroisoquinoline
4b.
Obtained in 37% yield (from amphetamine) as an oil. The first
chromatography fraction yielded the known 2-chlorobenzo-
nitrile (46%). The NMR spectra of compound 4b indicates the
existence of several conformations with half lives in the range
of NMR time measurement. This does complicate the carbon
spectrum. νmax (KBr)/cmϪ1 3493, 2959, 2937, 1615; H: 1.52
1
(s (br), 3H, CH2), 2.73 (m, 1H, ½ CH2), 2.89 (m, 1H, ½ CH2),
3.7 (m (br), 1H, CH), 6.92 (d, 1H, J = 7.8), 7.14–7.45 (m, 7H);
13C: 23.0 (br), 34.4 (br), 54.2 (br), 127.7, 128.0, 128.2, 128.8,
129.6, 129.8, 129.9, 130.7, 130.8, 130.9, 131.1, 131.3, 131.6,
131.8, 132.1, 132.3, 133.9, 138.0 (br), 139.6, 166.3 (br); m/z
256.0904 (Mϩ ϩ H, C16H15NCl requires 256.0893).
1-(2-Chlorophenyl)-3-hydroxymethylisoquinoline 8
Compound 6b (0.25 g, 0.92 mmol) and trifluoroacetic
anhydride (1.96 ml, 13.9 mmol) were refluxed in 1,2-dichloro-
benzene for 2 hours. This was concentrated to dryness, treated
with a mixture of ethanol (20 ml) and 1 M sodium hydroxide
(20 ml) for 30 minutes. The resulting solution was extracted
with dichloromethane, the organic phase was washed with
water dried over magnesium sulfate and concentrated to dry-
ness. The residue was chromatographed over silica gel
(dichloromethane–ethanol 99 : 1) to give alcohol 8 (0.17 g, 68%)
1-(2-Chlorophenyl)isoquinoline 5a
In a Dean–Stark apparatus, the compound 4a (6 g, 24.8 mmol)
and manganese() oxide (10 g, 124 mmol) were refluxed
in benzene (500 ml) for four days in the course of which
three more portions of manganese oxide were added and reac-
tion samples were monitored by NMR. After removal of the
solvent, the crude residue was chromatographed over silica
gel (dichloromethane–ethanol 98 : 2) yielding compound 5a
(4.32 g, 72%) as an oil. νmax (KBr)/cmϪ1 3051, 1622, 1584, 1558;
1H: 7.32–7.47 (m, 5H), 7.55 (d, 1H, J = 9.0), 7.58–7.64 (m, 2H),
7.81 (d, 1H, J = 8.3), 8.54 (d, 1H, J = 5.9); 13C: 118.9, 125.1,
125.2, 125.5, 125.7, 127.52, 127.9, 128.1, 128.5, 129.5, 131.6,
134.6, 136.5, 140.3, 157.0; m/z 240.0574 (Mϩ ϩ H, C15H11NCl
requires 240.0579).
1
as a wax. νmax (KBr)/cmϪ1 3200, 3058, 1626, 1594, 1562; H:
4.84 (s, 2H, CH2), 7.29–7.45 (m, 5H), 7.51–7.62 (m, 3H), 7.76
(d, 1H, J = 8.2); 13C: 66.7, 118.6, 128.2, 128.6, 128.8, 129.1,
131.7, 132.3, 133.1, 135.1, 138.7, 139.8, 154.0, 160.1; m/z
268.0529 (Mϩ Ϫ H, C16H11NOCl requires 268.0530).
1-(2-Chlorophenyl)isoquinoline-3-carboxylic acid 9
1-(2-Chlorophenyl)-3-methylisoquinoline 5b
Aldehyde 7 (0.6 g, 2.24 mmol), silver nitrate (0.95 g, 5.61 mmol)
and sodium hydroxide (0.72 g, 17.9 mmol) were stirred in a
mixture of ethanol (40 ml) and water (40 ml) for 2 days. The
ethanol was removed in vacuo, the resulting aqueous phase was
made acidic with 1 M hydrochloric acid and extracted with
dichloromethane. The organic layer was washed with water
and concentrated to dryness. The residue was recrystallized in
heptane to yield acid 9 (0.52 g, 82%). Starting from alcohol 8,
using twice the amount of reagents, a similar yield of acid 9
was obtained. This acid was also obtained in 95% yield from
ester 16 which was treated in boiling 50% aqueous ethanol with
4 equivalents of sodium hydroxide for one hour followed by the
work up described above. Mp = 191 ЊC. νmax (KBr)/cmϪ1 3509,
Compound 4b (5.7 g, 22.3 mmol) and sulfur (3.5 g, 111 mmol)
in decalin (150 ml) were refluxed for 8 hours. After removal of
the solvent, the crude residue was chromatographed over silica
gel (dichloromethane) yielding compound 5b (3.71 g, 65%) as a
wax. νmax (KBr)/cmϪ1 3069, 3052, 1766, 1738, 1717; 1H: 2.73 (s,
3H, CH3), 7.36–7.56 (m, 8H), 7.77 (d, 1H, J = 9.1); 13C: 23.9,
118.3, 125.0, 125.9, 126.0, 126.5, 126.7, 129.3, 129.35, 129.7,
130.9, 133.0, 136.6, 138.1, 150.4, 157.8; m/z 254.0745 (Mϩ ϩ H,
C16H13NCl requires 254.0737).
3,4-Dihydroisoquinoline N-oxides 6a, b
To a solution of 3,4-dihydroisoquinolines 5a or 5b (4.2 mmol)
in dichloromethane (150 ml) was added 70% 2-chloroperoxy-
benzoic acid (2.1 g, 8.51 mmol). The solution was stirred over-
night, and washed with a 1 M sodium hydroxide solution and
water. The resulting organic phase was dried over magnesium
sulfate and concentrated to dryness. The residue was chromato-
1
2618, 2364, 1700; H: 7.39–7.78 (m, 7H), 8.05 (d, 1H, J = 8.2),
8.67 (s, 1H); 13C: 123.2, 127.3, 128.1, 129.2, 129.4, 130.4, 130.6,
131.0, 131.7, 132.1, 133.7, 137.0, 137.1, 139.0, 158.3, 165.3;
m/z (C.I.) 284–286; Anal. (C16H10NClO2): Calc: C: 67.74,
H: 3.55, N: 4.94, found: C: 67.77, H: 3.68, N: 4.70%.
J. Chem. Soc., Perkin Trans. 1, 2002, 529–532
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1-Hydroxy-3,4-dihydroisoquinoline-3-carboxylic acid methyl
ester 11
of potassium phosphate (0.13 g, 0.61 mmol) and 2-chloro-
phenylboronic acid (0.095 g, 0.61 mmol) were added and the
heating was continued for 5 hours (1H NMR monitoring of the
reaction samples was used to insure its completion). The sus-
pension was then concentrated to dryness and dispersed in
water. This was extracted with dichloromethane, the organic
phase was washed with water, dried over magnesium sulfate and
concentrated to dryness. The residue was chromatographed
over silica gel eluting first with dichloromethane to remove
some unidentified polyarylated compounds and volatile 2-
chlorophenol 17, and then dichloromethane–ethanol 99 : 1 to
provide 16 (0.25 g, 90%). Mp = 167 ЊC (heptane); νmax (KBr)/
Acid 1017 (1.5 g, 7.7 mmol) and one drop of concentrated
sulfuric acid were heated in methanol (100 ml) for 8 hours. The
solvent was removed in vacuo and the residue dissolved in
dichloromethane. This organic phase was washed with water,
dried over magnesium sulfate, then concentrated to dryness to
provide ester 11 as a solid which was used without further puri-
fication (1.5 g, 93%). νmax (KBr)/cmϪ1 3210, 1748, 1667; 1H: 3.21
(dd, 1H, J = 9.2, 15.6, ½CH2), 3.34 (dd, 1H, J = 5.1, 15.6,
½CH2), 3.83 (s, 3H, OCH3), 4.42 (m, 1H, CH), 6.48 (s (br), 1H,
NH), 7.23 (d, 1H, J = 7.9), 7.38 (m, 1H), 7.48 (m, 1H), 8.08 (d,
1H, J = 7.8); 13C: 31.0, 52.8, 52.9, 127.3, 127.4, 128.0, 128.3,
132.4, 136.1, 162.2, 170.9; m/z 206.0817 (Mϩ ϩ H, C11H11NO3
requires 206.0817).
1
cmϪ1 3339, 1715; H: 4.04 (s, 3H, OCH3), 7.40–7.46 (m, 4H),
7.63–7.66 (m, 2H), 7.77 (m, 1H), 8.03 (d, 1H, J = 8.2), 8.66
(s, 1H); 13C: 52.9, 124.2, 126.9, 127.5, 128.3, 128.7, 129.6, 130.1,
130.9, 131.5, 133.4, 135.9, 137.7, 140.9, 159.2, 166.4; Anal.
(C17H12NClO2): Calc: C: 68.58, H: 4.06, N: 4.7, Cl: 11.91,
found: C: 68.48, H: 4.04, N: 4.70, Cl: 11.90%.
1-Hydroxyisoquinoline-3-carboxylic acid methyl ester 12
Ester 11 (6 g, 29.2 mmol) and palladium over charcoal (10%,
1.55 g, 1.4 mmol) were refluxed in diphenyl ether (150 ml) over-
night. After concentration to dryness (care should be taken as
compound 12 will sublime if the last remnant of diphenyl ether
is removed), the residue was chromatographed over silica gel
(dichloromethane–ethanol 99 : 1) to afford ester 12 (4.3 g, 72%).
Mp = 163 ЊC (ethyl acetate–heptane) (Lit.26 = 161–162 ЊC); νmax
Acknowledgements
Dr. Daniel Dauzonne is gratefully acknowledged for the critical
reading of the manuscript.
References
1
(KBr)/cmϪ1 3172, 3087, 1728, 1666, 1605; H and 13C spectra
were identical with the reported16 data.
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Preparation of 1-halogeno derivatives 13 and 14
Compound 12 (2.05 g, 10.1 mmol), potassium carbonate (4.2 g,
30.3 mmol) and the corresponding trihalogenated phosphorus
oxide (30.3 mmol) were heated to reflux in dry acetonitrile
(150 ml). The reaction went to completion in 90 minutes in the
case of 14, whereas another portion of phosphorus oxychloride
(20.2 mmol) and potassium carbonate (20.2 mmol) had to be
added after 10 hours, and the reflux resumed for an additional
4 hours to complete the preparation of 13. The resulting sus-
pension was then concentrated to dryness, the residue was
cautiously dispersed in water and the insoluble material was
filtered off, washed with water, dried and recrystallized in
cyclohexane to yield compound 13 or 14.
1-Chloroisoquinoline-3-carboxylic acid methyl ester 13. (85%
yield). Mp = 114 ЊC (Lit.16 = 118–119 ЊC); νmax (KBr)/cmϪ1 3224,
13 D. A. Walsh, L. F. Sancilio and D. L. Reese, J. Med. Chem., 1978, 21,
1
2508, 1714, 1255; H and 13C spectra were identical with the
582.
reported16 data; Anal. (C11H8NClO2): Calc: C: 59.61, H: 3.64,
N: 6.32, Cl: 16.00, found: C: 59.78, H: 3.64, N: 6.38, Cl: 16.19%.
14 V. Bockelheide and W. J. Linn, J. Am. Chem. Soc., 1954, 76, 1286.
15 C. Fontenas, E. Byan, H. Aït Haddour and G. C. A. Balavoine,
Synth. Commun., 1995, 22, 629.
16 S. C. Tucker, J. M. Brown, J. Oakes and D. Thornthwaite,
Tetrahedron, 2001, 57, 2545.
17 P. Krogsgaard-Larsen, E. Ø. Nielsen and D. R. Curtis, J. Med.
Chem., 1984, 27, 585.
18 G. E. Hein and C. Niemann, J. Am. Chem. Soc., 1962, 84, 4487.
19 J. Heibl, H. Kollman, S. H. Levinson, P. Offen, S. B. Shetzline and
R. Badlani, Tetrahedron Lett., 1999, 40, 7935.
20 N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457.
21 A. Suzuki, J. Organomet. Chem., 1999, 576, 147.
22 D. Muller and J.-P. Fleury, Tetrahedron Lett., 1991, 32, 2229.
23 Y. Fukuyama, Y. Kiriyama and M. Kodama, Tetrahedron Lett.,
1993, 34, 7637.
24 M. Moreno-Mañas, M. Pérez and R. Pleixats, J. Org. Chem., 1996,
61, 2346.
25 Y. L. Janin, J. Chiki, M. Legraverend, C. Huel and E. Bisagni,
Tetrahedron, 1999, 55, 12797.
26 E. J. Stiller, J. Chem. Soc., 1937, 473.
1-Bromoisoquinoline-3-carboxylic acid methyl ester 14. (82%
yield). Mp = 125 ЊC; νmax (KBr)/cmϪ1 3510, 2357, 1717, 1251;
1H: 4.02 (s, 3H, OCH3), 7.81 (m, 2H), 7.96 (m, 1H), 8.37 (m,
1H), 8.52 (s, 1H, CH-4); 13C: 52.9, 124.4, 128.4, 129.0, 130.3,
130.9, 131.9, 136.7, 140.9, 145.3, 164.9; Anal. (C11H8NBrO2):
Calc: C: 49.65, H: 3.03, N: 5.26, found: C: 49.81, H: 3.08,
N: 5.32%.
1-(2-Chlorophenyl)isoquinoline-3-carboxylic acid methyl ester 16
Compound 14 (0.25 g, 0.93 mmol), potassium phosphate
(0.26 g, 1.22 mmol), tetrakis(triphenylphosphine)palladium
(0.03 g, 0.028 mmol) and 2-chlorophenylboronic acid 15
(0.19 g, 1.22 mmol) in dry DMF (20 ml) were heated at 80 ЊC
overnight under an argon atmosphere. Supplementary portions
532
J. Chem. Soc., Perkin Trans. 1, 2002, 529–532