Application of the heck reaction for the synthesis of 1-alkoxyisoquinoline- 3-carboxylic acids esters

Article abstract of DOI:10.1007/s10593-011-0844-7

It has been shown that the cyclization of the methyl 2-(2,2,2- trifluoroacetylamino)acrylate arylation product using methyl 4,6-dichloro-2-iodobenzoate gives the corresponding 1-methoxyisoquinoline-3- carboxylic acid ester through loss of water rather than methanol. This feature of the condensation has been used for the synthesis of methyl 1-(tert-butoxycarbonylmethoxy)isoquinoline-3-carboxylate.

Full text of DOI:10.1007/s10593-011-0844-7

Chemistry of Heterocyclic Compounds, Vol. 47, No. 7, October 2011 (Russian original Vol. 47, No. 7, July, 2011)
APPLICATION OF THE HECK REACTION
FOR THE SYNTHESIS OF
1-ALKOXYISOQUINOLINE-
3-CARBOXYLIC ACIDS ESTERS
A. Ture1, K. Rubina1, E. Rozhkov1, and V. Kauss1*
It has been shown that the cyclization of the methyl 2-(2,2,2-trifluoroacetylamino)acrylate arylation
product using methyl 4,6-dichloro-2-iodobenzoate gives the corresponding 1-methoxyisoquinoline-
3-carboxylic acid ester through loss of water rather than methanol. This feature of the condensation has
been used for the synthesis of methyl 1-(tert-butoxycarbonylmethoxy)isoquinoline-3-carboxylate.
Keywords: 2-iodobenzoic acids, methyl 2-(2,2,2-trifluoroacetylamino)acrylate, 1-oxo-1,2-dihydro-
quinoline-3-carboxylic acid, condensation, Heck reaction.
The isoquinoline-3-carboxylic acid structure has attracted the attention of chemists to this time due to
the many variants of its modification at different isoquinoline positions and also the possibility of converting the
carboxyl group into esters, amides, and heterocycles. For instance, esters of 2,4,6-substituted isoquinoline-
3-carboxylic acids have been used in the development of novel protein kinase inhibitors [1]. Selective inhibition
of phosphodiesterase type 5 has been found in a series of 1,4,6,7-substituted isoquinoline-3-carboxylic acids [2].
1-Arylisoquinoline-3-carboxylic acid dialkylamide PK11195 (ligand of peripheral benzodiazepine receptors) is
a known chemical biomarker of neurodegeneration [3]. A recent synthesis of 1-aryl-substituted isoquinolines
involves the use of the Suzuki reaction [4] and is now used for the preparation of PK11195 [5] and its analogs
[6]. The most suitable starting materials for the Suzuki reaction are 1-halo-substituted isoquinoline-3-carboxylic
acid esters which are readily prepared from the corresponding 1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid
esters. The main methods for the synthesis of such compounds are condensation of 1-isochromenones with
ammonia or with amines [7, 8] or the reaction of o-formylbenzoic acids with derivatives of glycine or its cyclic
analogs [9–11] or with nitrogen-containing Horner-Wadsworth-Emmons reagents [12, 13].
A more attractive method for the synthesis of 1-oxo-1,2-dihydroisoquinolines has recently appeared, i.e.
the tandem Heck reaction [14] of 2-(acetylamino)acrylates with o-iodobenzoic acid esters and their subsequent
cyclization [15]. This route has already been used in the preparation of compound PK11195 [5] and also for
development of solid-phase synthetic methods [16]. The indicated method allows the preparation of 1-oxo-
1,2-dihydroisoquinoline-3-carboxylic acid esters unsubstituted in the benzene ring in 60–65% yields.
_______
*To whom correspondence should be addressed, e-mail: valerjan@osi.lv.
1Latvian Institute for Organic Synthesis, 21 Aizkraukles St., Riga LV-1006, Latvia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1024–1031, July, 2011. Original
article submitted June 13, 2011.
838
0009-3122/11/4707-0838©2011 Springer Science+Business Media, Inc.

Within a medicinal chemistry project, we were interested in a convenient synthetic method for isoquino-
line-3-carboxylic acid esters containing a halogen atom (preferable in positions 6, 7, and 8) as well as
intermediate products suitable for subsequent functionalization at the C-1 atom. For the preparation of halo-
substituted 1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid esters of interest, we selected the Heck reaction
[15] since the halo-substituted o-formylbenzoic acids needed for traditional preparative methods were mostly
difficult to obtain and only through multistage syntheses.
The starting iodide 3 was prepared from the corresponding anthranilic acid 1a [17] by the standard
Sandmeyer reaction and subsequent esterification of the iodobenzoic acid 2a.
R1
R1
R1
R2OH
or
CO2R2
I
R
CO2H
NH2
R
CO2H
I
R
R2Br
NaNO2/KI
Cl
Cl
Cl
1a,b
2a,b
3, 4a,b
1, 2, 4 a R = H, R1 = Cl; 1, 2, 4 b R = Cl, R1 = H; 4a,b R2 = CH2COOBu-t; 3 R = H, R1 = Cl, R2 = Me
Arylation of acrylate 5a by iodide 3 was carried out by the method given in [15] with optimized condi-
tions reported by T. Jeffery [18]. Liquid chromatography–mass spectrometry pointed to the formation of several
products but some of them could not be determined unambiguously because of low solubility and weak
ionization. The target ester 6a was obtained in only 23% yield together with its hydrolysis product 7 (1%). The
use of bases other than sodium bicarbonate (potassium or cesium carbonate, triethylamine, diisopropylethyl-
amine) led to a lower yield of the isoquinolone 6a in all cases. We proposed that the yield of the target product
6a would increase by changing the acetyl group in the acrylate 5a for trifluoroacetyl since a better leaving group
could assist the cyclization. Separation of the mixture of products of the reaction of iodide 3 with acrylate 5b
[19] showed that the main reaction product is the acyclic diester 8 (52% yield). The yield of the isoquinolone
carboxylic acid 7 was 5%, the ester 6a could not be separated. To our surprise, the main product of the
cyclization step proved to be 1-methoxyisoquinoline 9 in 25% yield. The overall yield of compounds 7, 8, and 9
was 82% hence the Heck reaction under the Jeffery conditions [18] proved very efficient.
The proposal that the Heck reaction product 8 can exist as a mixture of (Z)- and (E)-isomers, the latter of
which cannot cyclize to isoquinolone 6a, could not be confirmed. The structure of the (Z)-isomer of the diester 8
was proved by the presence of an interaction between the proton at atom C-1' with atom C-3' (HMBC method,
3J(H–C) ~4 Hz, corresponding to a cis configuration) and with the ester methyl group at atom C-2' (the Overhauser
effect). Refluxing diester 8 in ethanol in the presence of sodium ethylate gives isoquinolone 6a (35%) but
complete conversion of diester 8 could not be achieved. The mechanism of formation of the 1-methoxy-
isoquinoline 9 with cyclization of the intermediate diester 8 has remained unclear and needs additional study.
However, the actual retention of the methoxy group during cyclization suggested that the exchange of the
methyl group of the ester in iodide 3 for another alkyl group (including one functionally substituted) leads to a
novel method for synthesizing 1-alkoxyisoquinolines. The importance of this finding is underlined by the fact
that all of the reported examples of the alkylation of isoquinolines occur unselectively to give a mixture of
O-and N-alkyl derivatives with the latter predominating. Only in a single patent a selective alkylation of an
isoquinolone with the use of benzyl bromide to give a 94% yield of 1-benzyloxyisoquinoline has been reported
[20]. Our attempts to O-alkylate isoquinolone 6a using tert-butyl bromoacetate gave hardly separable mixture of
products with a low conversion of the starting compound 6a. The O-alkylation product 10a is a very attractive
intermediate for the preparation of novel 1-substituted isoquinoline-3-carboxylic acids and their derivatives.
839

Cl
CO2Me
I
CO2Me
+
NHCOR
Cl
3
5a,b
Pd(OAc)2,
TBAB,
NaHCO3
5a
5b
Cl
Cl
O
CO2Me
NHCOCF3
NH
CO2Me
Cl
CO2Me
Cl
6a
8
+
+
OMe
N
Cl
Cl
O
7
NH
+
Cl
CO2Me
CO2H
Cl
7
9
5 a R = Me, b R = CF3
O
O
OBu-
t
O
O
OBu-t
Pd(OAc)2,
TBAB,
NaHCO3
R1
R1
CO2Me
R
R
N
O
6a,b
+
+
NHCOCF3
CO2Me
Cl
Cl
I
10a,b
4a,b
5b
a R = H, R1 = Cl; b R = Cl; R1 = H
Next, we undertook to study the possible preparation of compounds 10a,b under the conditions for for-
mation of isoquinoline 9. The necessary starting iodides 4a,b, containing a tert-butoxycarbonylmethyl ester
group, were prepared from the corresponding iodobenzoic acids 2a,b. In turn, the acid 2b was synthesized from
anthranilic acid 1b according to [21]. Use of iodides 4a,b in the Heck reaction with acrylate 5b gave the diesters
10a,b although in low yields (24 and 13% respectively). However, the isoquinolones 6a (12%) and 6b (47%)
were also separated and these can be used as valuable starting materials in the synthesis of 1-substituted
isoquinoline-3-carboxylic acids.
840

In conclusion, we have developed an original, single stage method for the synthesis of 1-alkoxy-
isoquinoline-3-carboxylic acids esters via a Heck reaction of the corresponding alkyl o-iodobenzoates and
methyl 2-(2,2,2-trifluoroacetylamino)acrylate with simultaneous ring closure of the intermediate product.
EXPERIMENTAL
1H and 13C NMR spectra were recorded on a Varian Mercury-400 instrument (400 and 100 MHz respec-
tively) for compounds 2a,b, 3, and 4a,b and on a Varian Unity-600 instrument (600 and 150 MHz respectively)
for compounds 6a,b, 7–9, and 10a,b with HMDS as internal standard at  = 0.05 ppm. In recording HMBC,
1
HSQC, and NOESY 2D spectra, a 4096×1024 matrix was used which provided for H 2max = 250 ms recorded
along the F2 axis and 1max = 100 ms along the F1 axis. In order to improve the relative signal to noise, the
matrix of Fourier transformed data was carried out to zero twice and expanded in a cosine function. The mixing
time in the 2D-NOESY was 1 s. ESI–MS mass spectra (inductively coupled mass spectrometry) were performed
on a Micromass Quatro MicroTM API instrument in MeCN or MeOH with HCOOH. Monitoring of the reaction
course was carried out by TLC on Merck Kieselgel plates and revealed in UV light. Analysis of the reaction
mixtures was performed by liquid chromatography–mass spectrometer (liquid chromatograph Shimadzu
CBM-20A, mass spectrometer Applied Biosystems API 2000). Preparative column chromatography used Merck
Kieselgel grade silica gel (0.060–0.200 mm). Reagents and materials used in the experiments were obtained
from the companies Acros, Aldrich, and Alfa Aesar.
4,6-Dichloro-2-iodobenzoic Acid (2a). A solution of NaNO2 (1.7 g, 24.6 mmol) in water (5 ml) was
added dropwise at -2 ºC with stirring to a suspension of 2-amino-4,6-dichlorobenzoic acid (5 g, 24.3 mmol) in
3.5 M HCl (1000 ml). The mixture was stirred for 1 h at -2 to 0 ºC, cooling removed, and a solution of KI (4.1 g,
24.7 mmol) in water (5 ml) was added dropwise. The reaction mixture was heated to 80 ºC and heating was then
removed. The product was stirred for 18 h and the precipitate formed was filtered off, washed with water and
1
dried in air to give compound 2a (3 g, 39%). H NMR spectrum (DMSO-d6), , ppm (J, Hz): 7.78 (1H, d,
13
J = 2.0, H Ar); 7.98 (1H, d, J = 2.0, H Ar). C NMR spectrum (DMSO-d6), , ppm: 93.6 (C-2); 128.6 (C-1),
129.4 (C-3); 134.5 (C-6), 136.6 (C-5); 139.4 (C-4); 167.1 (C=O).
4,5-Dichloro-2-iodobenzoic Acid (2b). Obtained similarly to compound 2a from 2-amino-
4,5-dichlorobenzoic acid (2.21 g, 10.7 mmol), NaNO2 (0.55 g, 8 mmol), and KI (1.32 g, 8 mmol) to give
1
compound 2b as a white powder with mp 142–145ºC (2.15 g, 69%). H NMR spectrum (DMSO-d6), , ppm:
13
7.91 (1H, s, H Ar); 8.26 (1H, s, H Ar). C NMR spectrum (DMSO-d6), , ppm: 93.1 (C-2); 130.9 (C-1); 131.2
(C-6); 134.2 (C-3); 137.1 (C-5); 141.2 (C-4); 166.1 (C=O). Found, %: C 26.79; H 1.15. C7H3Cl2IO2. Calculated,
%: C 26.53; H 0.95.
Methyl 4,6-Dichloro-2-iodobenzoate (3). A mixture of compound 2a (4 g, 12.6 mmol) and thionyl
chloride (20 ml) was refluxed for 2 h and then evaporated to dryness. The residue was dissolved in dichloro-
methane (30 ml), absolute MeOH (1.5 ml) and triethylamine (5.33 ml) were added dropwise, and the mixture
was stirred at room temperature for 3 h. The reaction product was washed with water and the organic phase was
separated, dried over anhydrous sodium sulfate, and then evaporated. The residue was purified by column
chromatography on silica gel eluting with a 4:1 mixture of hexane and ethyl acetate to give compound 3a (2.6 g,
1
63%) as a light-yellow powder with mp 152–155 ºC. H NMR spectrum (CDCl3), , ppm (J, Hz): 3.97 (3H, s,
13
OCH3); 7.40 (1H, d, J = 2.0, H Ar); 7.73 (1H, d, J = 2.0, H Ar). C NMR spectrum (CDCl3), , ppm: 53.2
(CH3); 91.9 (C-2); 127.99 (C-1); 129.1 (C-3); 131.5 (C-6); 136.2 (C-5); 138.2 (C-4); 166.4 (C=O). Found, %:
C 29.92; H 1.55. C8H5Cl2IO2·0.2EtOAc. Calculated, %: C 31.32; H 1.91.
tert-Butoxycarbonylmethyl 4,6-Dichloro-2-iodobenzoate (4a). A mixture of compound 2a (9.25 g,
29.2 mmol), K2CO3 (4.03 g, 29.2 mmol), and tert-butyl bromoacetate (4.28 ml, 29.2 mmol) in dry acetone
(150 ml) was refluxed for 3 h, cooled to room temperature, filtered, and the filtrate evaporated in vacuo. The raw
product was purified by column chromatography on silica gel eluting with a 10:1 mixture of hexane and ethyl
1
acetate to give compound 4a (7.4 g, 59%) as an oil. H NMR spectrum (CDCl3), , ppm (J, Hz): 1.51 (9H, s,
841

(CH3)3C); 4.75 (2H, s, CH2); 7.42 (1H, d, J = 2.0, H Ar); 7.75 (1H, d, J = 2.0, H Ar). 13C NMR spectrum
(CDCl3), , ppm: 28.1 ((CH3)3C); 62.6 (OCH2); 82.8 ((CH3)3C); 92.2 (C-2); 129.3 (C-1); 131.9 (C-3); 136.5
(C-6); 137.1 (C-5); 137.2 (C-4); 165.2 (C=O); 165.6 (C=O). Mass spectrum, m/z (Irel, %): 431 [M+H]+ (100).
tert-Butoxycarbonylmethyl 4,5-dichloro-2-iodobenzoate (4b) was prepared similarly to compound 4a
from compound 2b (1.35 g, 4.27 mmol), K2CO3 (0.43 g, 3.1 mmol), and tert-butyl bromoacetate (0.63 ml, 4.27
1
mmol) as an oil (1.1 g, 60%). H NMR spectrum (CDCl3, ppm: 1.49 (9H, s, (CH3)3C); 4.73 (2H, s, CH2);
8.05 (1H, s, H Ar); 7.75 (1H, s, H Ar). 13C NMR spectrum (CDCl3), , ppm: 28.4 ((CH3)3C); 61.2 (OCH2); 81.8
((CH3)3C); 90.69 (C-2); 131.9 (C-1); 132.0 (C-6); 132.9 (C-3); 136.1 (C-5); 141.6 (C-4); 162.9 (C=O); 165.4
(C=O). Mass spectrum, m/z (Irel, %): 431 [M+H]+ (100).
Methyl 6,8-Dichloro-1-oxo-1,2-dihydroisoquinoline-3-carboxylate (6a). The acrylate 5a (0.389 g,
2.72 mmol), tetrabutylammonium bromide (0.584 g, 1.81 mmol), NaHCO3 (0.381 g, 4.53 mmol), and Pd(OAc)2
(0.061 g, 0.27 mmol) were added with stirring under an argon atmosphere to a solution of compound 3 (0.6 g,
1.81 mmol) in DMF (5 ml). The mixture was stirred at 90 ºC for 24 h and cooled to room temperature. The
obtained heterogeneous mixture was filtered and the precipitate on the filter was washed with acetone to give
1
compound 6a (1.15 g, 23%) as a light-yellow powder with mp > 240ºC (decomp.). H NMR spectrum
(DMSO-d6), , ppm (J, Hz): 3.85 (3H, s, OCH3); 7.33 (1H, s, H-4); 7.73 (1H, d, J = 1.9, H-7); 8.00 (1H, d,
13
J = 1.9, H-5); 11.30 (1H, br. s, NH). C NMR spectrum (DMSO-d6), , ppm: 53.5 (CH3); 109.1 (C-3); 123.2
(C-8a); 127.5 (C-5); 131.3 (C-4a); 131.4 (C-7); 135.9 (C-8); 137.5 (C-6); 140.7 (C-4); 159.7 (N–C=O); 161.5
(O–C=O). Found, m/z: 271.9857 [M+H]+. C11H8O3NCl2. Calculated: 271.9881.
Reaction of Methyl 4,6-Dichloro-2-iodobenzoate (3) with Methyl 2-(2,2,2-Trifluoroacetylamino)-
acrylate (General Method). The acrylate 5b (0.106 g, 0.54 mmol), tetrabutylammonium bromide (0.116 g,
0.36 mmol), sodium bicarbonate (0.076 g, 0.9 mmol), and palladium diacetate (0.02 g, 0.09 mmol) were added
with stirring under an argon atmosphere to a solution of compound 3 (0.116 g, 0.36 mmol) in DMF (5 ml). The
mixture was stirred for 20 h at 90 ºC, cooled to room temperature, and diluted with water (30 ml). The
heterogeneous mixture obtained was extracted with ethyl acetate (2×20 ml) and the organic phase was washed
with saturated sodium chloride solution (4×20 ml), dried over sodium sulfate, and the solvent evaporated to
dryness in vacuo. The reaction products 7–9 were separated by column chromatography on silica gel eluting
with a 1:5 mixture of ethyl acetate and hexane or with dichloromethane.
6,8-Dichloro-1-oxo-1,2-dihydroisoquinoline-3-carboxylic Acid (7). White powder (0.008 g, 5%); mp
1
> 240 ºC (decomp.). H NMR spectrum (DMSO-d6), , ppm (J, Hz): 7.26 (1H, s, H-4); 7.69 (1H, d, J = 1.8,
H-7); 7.97 (1H, d, J = 1.8, H-5); 10.89 (1H, br. s, NH); 14.00 (1H, br. s, OH). 13C NMR spectrum (DMSO-d6),
 , ppm: 109.3 (C-4); 122.9 (C-8a); 127.3 (C-5); 131.0 (C-7); 132.9 (C-4a); 135.9 (C-8); 137.4 (C-6); 141.1
(C-3); 159.7 (C=O); 162.7 (C=O). Mass spectrum, m/z (Irel, %): 256 [M-H]+ (100).
Methyl 4,6-Dichloro-2-[(Z)-2-methoxycarbonyl-2-(2,2,2-trifluoroacetylamino)vinyl]benzoate (8).
Oil, yield 0.075 g (53%). 1H NMR spectrum (CDCl3), , ppm (J, Hz): 3.89 (3H, s, OCH3); 3.91 (3H, s, OCH3);
7.18 (1H, d, J = 1.8, H-3); 7.41 (1H, d, J = 1.8, H-5); 7.48 (1H, s, H vinyl). 13C NMR spectrum (CDCl3), , ppm:
1
53.2 (CH3); 53.5 (CH3); 115.3 (CF3, JC-F = 289.0); 125.2 (C-1'); 126.0 (C-3); 128.4 (C-2'); 130.1 (C-5); 130.8
(C-1); 133.1 (C-6); 134.5 (C-2); 136.4 (C-4); 154.4 (COCF3); 163.3 (C=O); 166.4 (C=O). Found, m/z: 421.9764
[M+Na]+. C14H10O5NCl2F3. Calculated: 421.9786.
Methyl 6,8-Dichloro-1-methoxyisoquinoline-3-carboxylate (9). Oil, yield 0.036 g (25%). H NMR spectrum
1
(CDCl3), , ppm (J, Hz): 3.97 (3H, s, OCH3); 4.17 (3H, s, OCH3); 7.62 (1H, d, J = 2.1, H-7); 7.71 (1H, d, J = 2.1,
13
H-5); 7.97 (1H, s, H-4). C NMR spectrum (CDCl3), , ppm: 52.8 (CO2CH3); 54.2 (OCH3); 117.5 (C-8a); 117.7
(C-4); 125.9 (C-5); 132.0 (C-7); 133.2 (C-8); 136.3 (C-6); 140.1 (C-4a); 140.7 (C-3); 160.32 (C-1); 165.55
(C=O). Mass spectrum, m/z (Irel, %): 286 [M+H]+ (100).
Reaction of tert-Butoxycarbonylmethyl 4,6-Dichloro-2-iodobenzoate (4a) with Methyl 2-(2,2,2-Tri-
fluoroacetylamino)acrylate (5b). Acrylate 5b (0.686 g, 3.48 mmol), tetrabutylammonium bromide (0.748 g,
2.32 mmol), sodium bicarbonate (0.487 g, 5.8 mmol), and palladium diacetate (0.13 g, 0.58 mmol) were added
with stirring under an argon atmosphere to a solution of compound 4a (1.0 g, 2.32 mmol) in DMF (5 ml). The
842

mixture was stirred for 18 h at 90 ºC, cooled to room temperature, and diluted with water (300 ml). The obtained
heterogeneous mixture was extracted with ethyl acetate (2×20 ml) and the organic phase was washed with
saturated sodium chloride solution (4×20 ml), dried over sodium sulfate, and solvent removed in vacuo. The
reaction products 6a and 10a were separated by column chromatography on silica gel eluting with a 1:5 mixture
of ethyl acetate and hexane.
Methyl 1-(1-tert-Butoxycarbonylmethoxy)-6,8-dichloroisoquinoline-3-carboxylate (10a). White
1
powder (0.2 g, 24%); mp > 130 ºC (decomp.). H NMR spectrum (DMSO-d6), , ppm (J, Hz): 1.38 (9H, s,
(CH3)3C); 3.86 (3H, s, OCH3); 4.96 (2H, s, CH2); 7.99 (1H, d, J = 2.0, H-7); 8.25 (1H, s, H-4); 8.31 (1H, d,
J = 2.0, H-5). 13C NMR spectrum (DMSO-d6), , ppm: 28.2 ((CH3)3C); 53.0 (OCH3); 64.1 (OCH2); 81.7
((CH3)3C); 116.9 (C-8a); 119.0 (C-4); 127.4 (C-5); 132.1(C-4a); 132.5 (C-7); 136.2 (C-6); 139.5 (C-8); 141.3
(C-3); 158.4 (C-1); 164.8(CO2CH3); 167.4 (CO2CH2). Mass spectrum, m/z (Irel, %): 386 [M+H]+ (100). Found,
%: C 52.05; H 4.29; N 3.50. C17H17Cl2NO5·0.5H2O. Calculated, %: C 51.66; H 4.59; N 3.54.
Reaction of tert-Butoxycarbonylmethyl 4,5-Dichloro-2-iodobenzoate (4b) with Methyl 2-(2,2,2-Tri-
fluoroacetylamino)acrylate (5b). Methyl 2-(2,2,2-trifluoroacetylamino)acrylate (0.089 g, 0.45 mmol),
tetrabutylammonium bromide (0.097 g, 0.3 mmol), sodium bicarbonate (0.063 g, 0.75 mmol), and palladium
diacetate (0.01 g, 0.045 mmol) were added with stirring under an argon atmosphere to a solution of compound
4b (0.13 g, 0.3 mmol) in DMF (5 ml). The mixture was stirred for 19 h at 90 ºC, cooled to room temperature,
and diluted with water (30 ml). The obtained heterogeneous mixture was filtered and the precipitate on the filter
was washed with water and then ethyl acetate and dried in air to give compound 6b. The filtrate was extracted
with ethyl acetate (3×40 ml) and the organic phase was washed with saturated sodium chloride solution
(2×30 ml) and water (2×20 ml), dried over sodium sulfate, and solvent removed in vacuo. The oily, dry product
of compound 10b was separated by column chromatography on silica gel eluting with dichloromethane.
Methyl 6,7-Dichloro-1-oxo-1,2-dihydroisoquinoline-3-carboxylate (6b). White powder (0.039 g,
1
47%) with mp˃230 ºC (decomp.). H NMR spectrum (DMSO-d6), , ppm: 3.86 (3H, s, OCH3); 7.41 (1H, s,
H-4); 8.27 (1H, s, H-7); 8.29 (1H, s, H-5); 11.55 (1H, br. s, NH). 13C NMR spectrum (DMSO-d6), , ppm: 53.5
(OCH3); 108.9 (C-4); 128.1 (C-8a); 129.0 (C-8); 130.5 (C-5); 131.0 (C-4a); 132.2 (C-7); 136.2 (C-3); 136.4
(C-6); 160.5 (N–C=O); 161.9 (O–C=O). Mass spectrum, m/z (Irel, %): 272 [M+H]+ (100). Found, %: C 45.28;
H 2.59; N 5.19. C11H7Cl2NO3·H2O. Calculated, %: C 45.54; H 3.13; N 4.83.
Methyl 1-(tert-Butoxycarbonylmethoxy)-6,7-dichloroisoquinoline-3-carboxylate (10b). Oil, yield
0.015 g (13%). 1H NMR spectrum (DMSO-d6), , ppm: 1.48 (9H, s, (CH3)3C); 3.96 (3H, s, OCH3); 5.04 (2H, s,
13
CH2); 7.98 (1H, s, H-5); 8.06 (1H, s, H-4); 8.48 (1H, s, H-8). C NMR spectrum (DMSO-d6), , ppm: 28.0
((CH3)3C); 52.7 (OCH3); 63.6 (OCH2); 82.3 ((CH3)3C); 117.8 (C-4); 119.9 (C-8a); 126.1 (C-8); 128.7 (C-5);
133.7 (C-7); 136.3 (C-4a); 136.6 (C-6); 139.7 (C-3); 158.3 (C-1); 165.5 (CO2CH3); 167.5 (CO2CH2). Mass
spectrum, m/z (Irel, %): 386 [M+H]+ (100).
This work has been supported by: European Social Fund within the National Program "Support for the
carrying out doctoral study program's and post-doctoral researches" project "Support for the development of
doctoral studies at Riga Technical University",
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