Improved synthesis of 1-chloro-6-methoxy-isoquinolin-3-ol and its derivatives

Article abstract of DOI:10.1080/00397910802517889

A convenient and efficient synthetic route to 1-chloro-6-methoxy- isoquinolin-3-ol and its derivatives is reported. This new method involves carboxylation of 4-methoxy-2-methylbenzonitrile, subsequent conversion of the resulting 2-cyano-5-methoxy-phenylac

Full text of DOI:10.1080/00397910802517889

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Improved Synthesis of
1-Chloro-6-methoxy-
isoquinolin-3-ol and Its
Derivatives
Zhizhen Barbara Zheng a , Alan Xiangdong Wang a ,
Paul Scola a & Stanley D'Andrea a
a Bristol-Myers Squibb, Discovery Chemistry,
Pharmaceutical Research Institute , Wallingford,
Connecticut, USA
Published online: 04 Mar 2009.
To cite this article: Zhizhen Barbara Zheng , Alan Xiangdong Wang , Paul Scola &
Stanley D'Andrea (2009) Improved Synthesis of 1-Chloro-6-methoxy-isoquinolin-3-ol
and Its Derivatives, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 39:7, 1264-1272
To link to this article: http://dx.doi.org/10.1080/00397910802517889
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Synthetic Communications1, 39: 1264–1272, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802517889
Improved Synthesis of 1-Chloro-6-methoxy-
isoquinolin-3-ol and Its Derivatives
Zhizhen Barbara Zheng, Alan Xiangdong Wang, Paul Scola,
and Stanley D’Andrea
Bristol-Myers Squibb, Discovery Chemistry, Pharmaceutical
Research Institute, Wallingford, Connecticut, USA
Abstract: A convenient and efficient synthetic route to 1-chloro-6-methoxy-
isoquinolin-3-ol and its derivatives is reported. This new method involves carbox-
ylation of 4-methoxy-2-methylbenzonitrile, subsequent conversion of the resulting
2-cyano-5-methoxy-phenylacetic acid to its acid chloride, and acid-promoted
cyclization of the 2-cyano-5-methoxy-phenyl-acetyl chloride. This procedure
offers a better overall yield than the previously reported route and is also less
hazardous and more reproducible.
Keywords: Carboxylation, cyclization, 1-chloro-6-methoxy-isoquinolin-3-ol,
4-methoxy-2-methylbenzonitrile
INTRODUCTION
A recent research project in our laboratory required a convenient synth-
esis of 1-chloro-6-methoxy-isoquinolin-3-ol. A literature search revealed
that there was just one reported route to this compound and its des-
methoxy derivative.[1,2] This synthetic route requires five steps and pro-
vides an overall yield of about 5.3% (Scheme 1). These steps include (1)
carboxylation of 3-methyl-4-nitroanisole 1 using diethyl oxalate in the
presence of sodium methoxide to give 5-methoxy-2-nitrophenylacetic
acid 2, (2) reduction of the nitro group with hydrogen in the presence
Received August 19, 2008.
Address correspondence to Zhizhen Barbara Zheng, Bristol-Myers Squibb,
Discovery Chemistry, Pharmaceutical Research Institute, 5 Research Parkway,
Wallingford, CT 06492, USA. E-mail: zhizhen.zheng@bms.com
1264

1-Chloro-6-methoxy-isoquinolin-3-ol
1265
Scheme 1. Previously published route to 4.
of 10% palladium=carbon to form 2-amino-5-methoxyphenylacetic acid,
(3) Sandmeyer reaction of 2-amino-5-methoxyphenylacetic acid to give 2-
cyano-5-methoxyphenylacetic acid 3, (4) conversion of 2-cyano-5-meth-
oxyphenylacetic acid to 2-cyano-5-methoxyphenylacetyl chloride by
treatment with phosphorus pentachloride, and (5) hydrogen chloride–
induced cyclization of 2-cyano-5-methoxyphenylacetyl chloride to form
1-chloro-6-methoxy-isoquinolin-3-ol 4.
RESULTS AND DISCUSSION
In our hands, the Sandmeyer reaction was not very reproducible, which
added to the difficulties in relying on this lengthy five-step procedure. We
report here a short, efficient synthesis of 1-chloro-6-methoxy-isoquinolin-
3-ol (4) (Scheme 2) and its subsequent use in the preparation of
isoquinolin-3-ol ethers.
Scheme 2. Improved route to 1-chloro-6-methoxy-isoquinolin-3-ol 4.

1266
Z. B. Zheng et al.
We avoided the potentially problematic Sandmeyer reaction by
starting with 4-methoxy-2-methylbenzonitrile 5, which has the requisite
cyano group already in place. Deprotonation[3] of 4-methoxy-2-methyl-
benzonitrile
5 using 1.4:1 lithium diisopropylamide (LDA)–1,3-
dimethyl-3,4,5,6-tetrahyde-2(1H)-pyrimidone (DMPU) in tetrahydro-
furan (THF) proceeded smoothly at ꢀ78 ꢁC. The benzylic anion was
treated with carbon dioxide to generate the desired acid 3. [Acylation of
the 4-methoxy-2-methylbenzonitrile anion with other electrophiles such
as methyl chloroformate gave a mixture of mono and dicarboxylation
products (4:1 mono–dicarboxylation)]. Pure 3 was easily isolated in 82%
yield by precipitating it from an acidic aqueous solution. Because the
benzylic protons in 3 were considered to be more acidic than the corre-
sponding position in the starting material 5, 2.4 eq. of LDA was used in
the reaction to prevent quenching of the anion of 5 by 3. We also noticed
that an aqueous quench of this reaction needs to be performed at ꢀ78 ꢁC
to avoid obtaining both the mono- and dicarboxylated products. How-
ever, the dicarboxylated product can be easily converted to the desired
monocarboxylated product 3 by treatment with trifluoroacetic acid
(TFA) at room temperature for 10–20 min.[4] Thus, 2-cyano-5-methoxy-
phenylacetic acid 3 was prepared in a single step in 82% yield without
the need for chromatographic purification. This synthesis of 3 is more
efficient and reproducible than the Sandmeyer route discussed pre-
viously.[1] It is also safer because it avoids the use of toxic cyanide salts
and potentially explosive diazonium compounds. Cyano-5-methoxyphe-
nylacetyl chloride 6 was obtained by treatment of 3 with thionyl chloride.
The acid chloride is then cyclized with commercially available 4 M
hydrogen chloride in dioxane at 60 ꢁC to form 1-chloro-6-methoxy-iso-
quinolin-3-ol, a process that presumably involves the intermediacy of
the benzimidoyl chloride.[1] This procedure is more convenient than the
literature conditions[2] in which 6 was dissolved in the highly peroxidiza-
bledi-n-butyl ether prior to treatment with hydrogen chloride gas. The
improved three-step synthesis of 1-chloro-6-methoxy-isoquinolin-3-ol 4
is straightforward and efficient with an overall yield of 70%.
We were also interested in alkylating and arylating 1-chloro-6-
methoxy-isoquinolin-3-ol. Therefore, 1-chloro-6-methoxy-isoquinolin-
3-ol (4) was treated with potassium carbonate and various electro-
philes (RX) in DMF to yield the alkylated products[5] (Scheme 3).
The alkylation conditions and yields are summarized in Table 1. Both
primary and second alkyl halides react with compound 4 to provide
the ethers in good yield.
Alkylation of compound 4 with primary halides required shorter
reaction time than the secondary halides. Benzylation was best carried
out patiently at room temperature using benzyl bromide.

1-Chloro-6-methoxy-isoquinolin-3-ol
1267
Scheme 3. Alkylation of 1-chloro-6-methoxy-isoquinolin-3-ol 4.
Table 1. Alkylation of phenol 4
Compound
RX
Temperature (ꢁC) Time (hours) Yield (%)
7
8
MeI
EtI
80
80
3
3
77
83
66
9
80
80
3
3
10
65
71
11
12
80
80
5
6
79
87
13
Rt
2 days
The arylation of 1-chloro-6-methoxy-isoquinolin-3-ol was accom-
plished in modest yield by a copper-promoted cross-coupling reaction
with phenylboronic acid as depicted in Scheme 4.[6]
In conclusion, we have developed an improved three-step synthesis of
1-chloro-6-methoxy-isoquinolin-3-ol that offers a better overall yield
than the previously reported procedure.[1,2] In addition, we have shown
Scheme 4. Arylation of 1-chloro-6-methoxy-isoquinolin-3-ol 4.

1268
Z. B. Zheng et al.
that alkylation and arylation of 1-chloro-6-methoxy-isoquinolin-3-ol 4
yields a variety of isoquinolin-3-ol ethers.
EXPERIMENTAL
Nuclear magnetic resonance (NMR) spectra were recorded on either a
Bruker 300 or 500 megahertz (MHz) spectrometer; the chemical shifts
(d) are reported in parts per million. Flash chromatography was carried
out on silica gel (SiO2). All liquid chromatography (LC) data were
recorded on a Shimadzu LC-10AS liquid chromatograph using a
SPD-10AV UV-vis detector, and mass spectrometry (MS) data were
determined with a Micromass Platform for LC in electrospray mode
(ES þ). Melting points were recorded on a EZ-Melt automated melt-
ing-point apparatus by Stanford Research Systems.
(2-Cyano-5-methoxy-phenyl)-acetic Acid (3)
A mixture of LDA (2.0 M in heptane=THF=ethyl benzene, 122.40 mL,
244.80 mmol) in 300 mL of THF was cooled to –78 ꢁC, and 21.60 mL
of DMPU [1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone] was
added slowly. The reaction was stirred for 5 min. A solution of
4-methoxy-2-methyl-benzonitrile (15.00 g, 102.0 mmol) in 20 mL of
THF was added, and the mixture was maintained at –78 ꢁC for 2 h to
form a deep red solution. Carbon dioxide gas was introduced into the
reaction mixture at –78 ꢁC until complete decolorization occurred and
the red solution had turned nearly colorless. Water (100 mL) was added
at –78 ꢁC, and the reaction mixture was warmed to rt. The reaction mix-
ture was extracted with 200 mL of ether, and the separated aqueous phase
was adjusted to pH 1 with 6 M HCl. A white solid precipitated from the
acidic aqueous solution and was collected by filtration, washed with H2O,
and dried in vacuo to give 16 g of 3 as an off-white solid (82%);
mp ¼ 213.1–214.5 ꢁC. 1H NMR (300 MHz, CD3OD) d 3.83 (s, 2H),
3.86 (s, 3H), 6.99 (m, 2H), 7.64 (d, J ¼ 8.42 Hz, 1H). HRMS calcd. for
[C10H9ClNO3 þ 1]þ: 192.0661; found: 192.0669.
(2-Cyano-5-methoxy-phenyl)-acetyl Chloride (6)
Ten mL of SOCl2 was added to a mixture of (2-cyano-5-methoxyphenyl)
acetic acid (3) (1.77 g, 9.26 mmol) in 10 mL of CH2Cl2. The mixture was
stirred at rt for 3 h and then placed in a refrigerator for 2 days before

1-Chloro-6-methoxy-isoquinolin-3-ol
1269
concentrating in vacuo to yield 1.90 g (98%) of the acid chloride 6,
an orange oil. This material was used in the next step without further
1
purification. H NMR (300 MHz, CDCl3) d 3.86 (m, 3H), 4.35 (s, 2H),
6.92 (m, 2H), 7.63 (d, J ¼ 8.78 Hz, 1H).
1-Chloro-6-methoxy-isoquinolin-3-ol (4)
First Procedure
A mixture of (2-cyano-5-methoxyphenyl)acetyl chloride (6) (18.00 g,
86.12 mmol) in 200 mL of 4 N HCl=dioxane was heated at 60 ꢁC for
6 h. The reaction mixture was cooled to rt and concentrated in vacuo
to afford a brown solid, which was recrystallized from EtOH to pro-
vide 10.00 g (56%) of pure 4 as an off-white solid (an additional 6.01 g
of impure 4 was recovered from the mother liquors); mp ¼ 203.2–
205.5 ꢁC, lit.[2] mp ¼ 211 ꢁC. 1H NMR (500 MHz, CD3OD) d 3.98
(s, 3H), 6.94 (s, 1H), 7.14 (m, 2H), 8.10 (d, J ¼ 9.16 Hz, 1H). HRMS
calcd. for [C10H8ClNO2 þ 1]þ: 210.0322; found: 210.0331.
Alternate Procedure
A solution of 2-(2-cyano-5-methoxyphenyl)acetyl chloride (6) (6.40g, 30.62
mmol) in 4 M HCl=1,4-dioxane (100 mL) was heated in a sealed vessel at
60 ꢁC with stirring overnight. After cooling to rt, the solids were collected
by filtration, and the filter cake washed thoroughly with EtOAc. The solid
was dried in vacuo to provide 6.14g (96%) of 4 as a fine, pale yellow powder.
General Procedure for Alkylation of 4
Preparation of 1-Chloro-3,6-dimethoxyisoquinoline (7)
Methyl iodide (607 mL, 0.95 mmol) and K2CO3 (0.13 g, 0.95 mmol) were
added to a mixture of 1-chloro-6-methoxy-isoquinolin-3-ol (4) (0.10 g,
0.48 mmol) in 3 mL of DMF. The mixture was heated at 80 ꢁC for 3 h,
cooled to rt, and concentrated in vacuo to afford a brown solid. The
crude product was purified by flash chromatography eluting with
10% EtOAc=hexane to isolate 82 mg (77%) of 7 as a white solid;
1
mp ¼ 135.1–136.5 ꢁC. H NMR (300 MHz, CDCl3) d 3.91 (s, 3H), 6.80
(s, 1H), 6.89 (d, J ¼ 2.56 Hz, 1H), 7.03 (dd, J ¼ 9.15, 2.56 Hz, 1H), 8.06
(d, J ¼ 9.51 Hz, 1H). HRMS calcd. for [C11H10ClNO2 þ 1]þ: 224.0478;
found: 224.0488.

1270
Z. B. Zheng et al.
1-Chloro-3-ethoxy-6-methoxyisoquinoline (8)
Compound 8 was prepared in a manner similar to that described previ-
ously to provide 188 mg (83%) of 8 as a tan solid, mp ¼ 89.0–90.8 ꢁC.
1H NMR (500 MHz, CDCl3) d 1.43 (t, J ¼ 7.02 Hz, 3H), 3.92 (m, 3H),
4.36 (q, J ¼ 7.02 Hz, 2H), 6.79 (s, 1H), 6.89 (d, J ¼ 2.44 Hz, 1H), 7.03
(dd, J ¼ 9.46, 2.44 Hz, 1H), 8.06 (d, J ¼ 9.16 Hz, 1H). HRMS calcd. for
[C12H12ClNO2 þ 1]þ: 238.0635; found: 238.0623.
1-Chloro-6-methoxy-3-propoxy-isoquinoline (9)
n-Propyl iodide (160 mg, 0.95 mmol) and K2CO3 (132 mg, 0.95 mmol)
were added to a mixture of 1-chloro-6-methoxy-isoquinolin-3-ol (4)
(100 mg, 0.48 mmol) in 2 mL of DMF. The mixture was heated at 80 ꢁC
for 2 h, cooled to rt, and concentrated in vacuo to obtain a brown solid.
The crude product was purified by flash chromatography, eluting with
10% EtOAc=hexane to isolate 80 mg (66%) of 9 as a colorless oil, which
1
was solidified as a white solid on standing at rt; mp ¼ 45.1–45.8 ꢁC. H
NMR (300 MHz, CDCl3) d 1.05 (t, J ¼ 7.32 Hz, 3H), 1.84 (m, 2H), 3.91
(s, 3H), 4.25 (t, J ¼ 6.77 Hz, 2H), 6.80 (s, 1H), 6.89 (d, J ¼ 2.56Hz, 1H),
7.03 (dd, J ¼ 9.15, 2.56Hz, 1H), 8.06 (d, J ¼ 9.51Hz, 1H). HRMS calcd
for [C13H14ClNO2 þ 1]þ: 252.0791; found: 252.0794.
4-(2-(1-Chloro-6-methoxyisoquinolin-3-yloxy)ethyl)morpholine (10)
4-(2-Chloroethyl)morpholine hydrochloride (222 mg, 1.49 mmol) and
K2CO3 (414 mg, 3.00 mmol) were added to a mixture of 1-chloro-6-meth-
oxy-isoquinolin-3-ol (4) (209 mg, 1.00 mmol) in 3 mL of DMF. The mix-
ture was heated at 80 ꢁC for 3 h, cooled to rt, and concentrated in vacuo
to obtain a brown solid. The crude product was then purified by flash
chromatography eluting with 10% methanol in ethyl acetate to isolate
1
210 mg (65%) of 10 as a white solid; mp ¼ 73.2–73.5 ꢁC. H NMR (300
MHz, CDCl3) d 2.59 (m, 4H), 2.81 (t, J ¼ 5.65 Hz, 2H), 3.69-3.75 (m,
4H), 3.91 (s, 3H), 4.48 (t, J ¼ 5.80 Hz, 2H), 6.84 (s, 1H), 6.88 (d,
J ¼ 2.14 Hz, 1H), 7.04 (dd, J ¼ 9.31, 2.29 Hz, 1H), 8.05 (d, J ¼ 9.46 Hz,
1H). HRMS calcd. for [C16H94ClNO2 þ 1]þ: 323.1162; found: 323.1172.
1-Chloro-3-isopropoxy-6-methoxy-isoquinoline (11)
Compound 11 was prepared from 1-chloro-6-methoxy-isoquinolin-3-ol
(4) (100 mg, 0.48 mmol), isopropyl iodide (138 mg, 0.95 mmol), and

1-Chloro-6-methoxy-isoquinolin-3-ol
1271
K2CO3 (132 mg, 0.95 mmol) in DMF as described in the general proce-
1
dure to give 85 mg (70%) of 11 as a yellow solid; mp ¼ 78.0–78.5 ꢁC. H
NMR (300 MHz, CDCl3) d 1.36 (s, 3H), 1.38 (s, 3H), 3.91 (s, 3H),
5.24 (m, 1H), 6.77 (s, 1H), 6.86 (d, J ¼ 2.20 Hz, 1H), 7.02 (dd, J ¼ 9.15,
2.56 Hz, 1H), 8.04 (d, J ¼ 9.15 Hz, 1H). HRMS calcd. for
[C13H14ClNO2 þ 1]þ: 252.0791; found: 252.0788.
1-Chloro-3-(cyclopentyloxy)-6-methoxyisoquinoline (12)
Cyclopentyl iodide (215 mg, 1.10 mmol) and K2CO3 (264 mg, 1.91 mmol)
were added to a mixture of 1-chloro-6-methoxy-isoquinolin-3-ol (4)
(209 mg, 1.00 mmol) in 2 mL of DMF. The mixture was heated at 80 ꢁC
for 6 h, cooled to rt, and concentrated in vacuo to obtain a brown solid.
The crude product was then purified by flash chromatography, eluting
with 10% ethyl acetate in hexane to isolate 220 mg (79%) of 12 as a white
1
solid; mp ¼ 86.0–87.5 ꢁC. H NMR (300 MHz, CDCl3) d 1.58–1.70 (m,
2H), 1.78–1.92 (m, 4H), 1.92–2.04 (m, 2H), 3.91 (s, 3H), 5.22–5.35 (m,
1H), 6.75 (s, 1H), 6.88 (d, J ¼ 2.14 Hz, 1H), 7.03 (dd, J ¼ 9.31, 2.29 Hz,
1H), 8.05 (d, J ¼ 9.16 Hz, 1H). HRMS calcd. for [C15H16ClNO2 þ 1]þ:
278.0948; found: 278.0954.
3-Benzyloxy-1-chloro-6-methoxy-isoquinoline (13)
Benzyl bromide (87 mg, 0.50 mmol) and K2CO3 (87 mg, 0.63 mmol) were
added to a mixture of 1-chloro-6-methoxy-isoquinolin-3-ol (4) (97 mg,
0.46 mmol) in 3 mL of DMF. The mixture was stirred at rt for 2 days,
and then concentrated in vacuo to obtain a brown solid. The crude pro-
duct was then purified by flash chromatography, eluting with 5% ethyl
acetate in hexane to isolate 120 mg (87%) of 13 as a white solid;
1
mp ¼ 116.8–117.5 ꢁC. H NMR (300 MHz, CDCl3) d 3.91 (s, 3H), 5.42
(s, 2H), 6.88 (d, J ¼ 2.56 Hz, 2H), 7.04 (dd, J ¼ 9.33, 2.38 Hz, 1H), 7.34
(m, 3H), 7.49 (d, J ¼ 6.59 Hz, 2H), 8.07 (d, J ¼ 9.15 Hz, 1H). HRMS
calcd. for [C17H14ClNO2 þ 1]þ: 300.0791; found: 300.0797.
1-Chloro-6-methoxy-3-phenoxy-isoquinoline (14)
Phenylboronic acid (580 mg, 4.75 mmol), Et3N (480 mg, 4.75 mmol), and
copper acetate (440 mg, 2.43 mmol) were added to a mixture of
1-chloro-6-methoxy-isoquinolin-3-ol (4) (500 mg, 2.39 mmol) in 10 mL
of CH2Cl2.. The mixture was stirred at rt for 18 h. It was then concentrated

1272
Z. B. Zheng et al.
in vacuo to obtain a brown-green solid. This crude product was purified
by flash chromatography, eluting with 10% EtOAc=hexane to isolate
1
50 mg (7.3%) of 14 as a white solid; mp ¼ 124.1–125.6 ꢁC. H NMR (500
MHz, CDCl3) d 3.89 (s, 3H), 6.81 (s, 1H), 6.90 (d, J ¼ 2.44 Hz, 1H),
7.13 (m, 3H), 7.21 (t, J ¼ 7.48 Hz, 1H), 7.41 (t, J ¼ 7.93 Hz, 2H), 8.13 (d,
J ¼ 9.16 Hz, 1H). HRMS calcd. for [C16H12ClNO2 þ 1]þ: 286.0635; found:
286.0629.
ACKNOWLEDGMENTS
The authors thank Dr. Nick Meanwell for providing helpful comments.
The authors also thank the Department of Analytical Services at Bris-
tol-Myers Squibb for their assistance with compound characterization.
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