Efficient access to C1- and C3-functionalized isoquinolines: Towards potential lanthanide ligands

Article abstract of DOI:10.1002/ejoc.201001691

Highly substituted isoquinolines have been synthesized by two different pathways using either a Pictet-Grams or a Bischler-Napieralski approach. While the first synthesis afforded C1-functionalizable 1,3-dimethylisoquinoline derivatives, the second approa

Full text of DOI:10.1002/ejoc.201001691

FULL PAPER
DOI: 10.1002/ejoc.201001691
Efficient Access to C1- and C3-Functionalized Isoquinolines: Towards Potential
Lanthanide Ligands
Fabien Caillé,[a,b] Frédéric Buron,[a] Éva Tóth,[b] and Franck Suzenet*[a]
Keywords: Nitrogen heterocycles / Fused-ring systems / Lanthanides
Highly substituted isoquinolines have been synthesized by
two different pathways using either a Pictet–Grams or a
lenging C3 position. Among the large variety of efficient
chemistry that can be independently or simultaneously per-
Bischler–Napieralski approach. While the first synthesis af- formed at the C1 and C3 positions of the isoquinoline ring,
forded C1-functionalizable 1,3-dimethylisoquinoline deriva-
tives, the second approach allowed the isolation of isoquino-
line derivatives bearing a reactive ester function at the chal-
1,3-dibromomethylisoquinoline derivatives have proven to
be efficient intermediates for the synthesis of highly valuable
ligands for lanthanide complexation.
substituted at the C1 position and, to a lesser extent, at the
C4 position are quite readily performed, functionalization
at the C3 position appears to be much more difficult.
As part of a research project on the development of lan-
thanide complexes as novel probes for optical and magnetic
resonance imaging,[18] access to polysubstituted isoquinol-
ines was of primary interest. Indeed, this scaffold shows
interesting luminescence properties,[19] and substitution by
electron-donating groups (EDG), like methoxy, on its ben-
zene ring could enhance its capacities.[20] Therefore, the iso-
quinoline core has to bear highly reactive groups at both
the C1 and C3 positions for further functionalization (Fig-
ure 1). Herein, we wish to report an efficient route to highly
substituted isoquinolines bearing reactive functions at the
C1 and challenging C3 positions. The strategy was applied
to the synthesis of original ligands for lanthanide complex-
ation.
Introduction
Isoquinoline derivatives are fundamental heterocyclic
compounds, and their abundance in many natural prod-
ucts[1] makes this scaffold a crucial building block for or-
ganic chemistry. They already proved to have medicinal im-
portance like the opium alkaloid papaverine.[2] As a result,
the synthesis of these heterocycles is of primary interest so
that a wide range of mimetics can be prepared for pharma-
ceuticals. Isoquinoline derivatives have found applications
in various types of medicines including anesthetics[3] and
anti-infectives[4] but also in other domains.[5,6] Conse-
quently, there has been tremendous interest in the design of
this scaffold, and research has focused on finding new
routes to synthesize this heteroaromatic core.
Many different routes have been explored to synthesize
dihydro- and tetrahydroisoquinolines,[7,8] but the available
syntheses of isoquinolines are less diversified,[9] and aroma-
tization is not trivial.[10] Since the early 1950s, various ap-
proaches to this heteroaromatic core have been proposed.
Among state-of-the-art approaches, the Pomeranz–
Fritsch[11] and the Bischler–Napieralki cyclizations[12] ap-
pear to be the most widely used reactions to design these
scaffolds. Other concerted electrocyclic reactions from allyl-
benzene,[13] nitrogen ylides,[14] or oximes[15] were also re-
ported. More recently, direct functionalization of the iso-
quinoline core[16] or metallocatalyzed routes[17] were de-
scribed. However, although the syntheses of isoquinolines
Figure 1. Polysubstituted isoquinolines bearing reactive moieties at
both the C1 and C3 positions towards potential lanthanide ligands.
[a] Institut de Chimie Organique et Analytique (ICOA),
University of Orléans,
UMR-CNRS 6005, rue de Chartres, 45063 Orléans cedex 2,
France
Results and Discussion
Tel: +33238494580
Considering that halogens in the benzylic position are
common leaving groups involved in many substitution pro-
cesses, we first focused our interest on the synthesis of a
E-mail: franck.suzenet@univ-orleans.fr
[b] Centre de Biophysique Moléculaire (CBM), UPR 4301 CNRS,
rue Charles Sadron, 45071 Orléans cedex 2, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001691.
1,3-dibromomethylisoquinoline intermediate (R1 = R2
=
2120
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Efficient Access to C1- and C3-Functionalized Isoquinolines
CH2Br, Figure 1). Benzylic bromination is known to be nium dioxide under harsh conditions. After N-oxidation of
readily performed under radical conditions from the corre- the isoquinoline ring, the N-oxide was submitted to re-
sponding methyl groups (R1 = R2 = CH3, Figure 1). This arrangement in the presence of acetic anhydride[25] followed
approach has also been described for unsubstituted 1,3-di- by basic treatment to afford a 1,3-dihydroxymethylisoquin-
methylisoquinolines,[13b,21] and we first focused our interest oline (Scheme 3).[26]
on the synthesis of 1,3-dimethylisoquinoline precursor 4
(Scheme 1). This key intermediate was obtained from the
Pictet–Grams modification of the Bischler–Napieralski ap-
proach.[22]
Scheme 3. Attempts to oxidize 4. Reagents and conditions:
(i) SeO2, 1,4-dioxane, reflux; (ii) NaBH4, MeOH, room temp.;
(iii) Ac2O, pyridine, DMAP, THF, room temp.; (iv) m-CPBA,
CH2Cl2, room temp.; (v) Ac2O, o-dichlorobenzene, reflux;
(vi) NaOH, EtOH, 50 °C.
To undertake this rearrangement, we planned to isolate
N-oxide isoquinoline 5 bearing a protected alcohol at the
C1 position. The synthesis was performed from compound
4; the methyl moiety was oxidized to an aldehyde group,
which was then reduced to an alcohol. Protection of the
primary alcohol followed by N-oxidation of the isoquino-
mediate 4. Reagents and conditions: (i) EtNO2, P(nBu)3, MeOH,
Scheme 1. Synthesis of substituted 1,3-dimethylisoquinoline inter-
line in the presence of m-CPBA rapidly afforded N-oxide 5
(Scheme 3). The key rearrangement with acetic anhydride
in refluxing o-dichlorobenzene followed by basic treatment
with potassium hydroxide was unfortunately unsuccessful
in our hands.
Considering the lack of reactivity of the methyl moiety at
the C3 position, we decided to develop an original synthetic
pathway to isoquinoline scaffolds already incorporating a
reactive ester group at this position. This function could be
introduced through diethyl aminomalonate[27] and subse-
quent decarboxylation (Scheme 4).
room temp.; (ii) TBDMSCl, imidazole, CH2Cl2, reflux; (iii) H2
(1 atm), Raney Ni, MeOH/NH3, 50 °C; (iv) Ac2O, pyridine,
CH2Cl2, room temp.; (v) POCl3, toluene, reflux.
The synthesis starts from commercially available 2,5-di-
methoxybenzaldehyde (1). Nitroaldolization was carried
out smoothly with nitroethane by using a catalytic amount
of tri-n-butylphosphane according to the method of
Weeden and Chilsholm.[23] The hydroxy group was immedi-
ately silylated without further purification to easily isolate
compound 2 in 66% yield over two steps. The nitro group
was then reduced by hydrogenation in the presence of
Raney nickel, and the resulting amine was acylated to af-
ford intermediate 3. Cyclization was carried out by using
phosphorus oxychloride in refluxing toluene. These condi-
tions allow both cyclization and elimination of the hydroxy
moiety to give desired 1,3-dimethylisoquinoline 4 in 62%
yield.
Bromination of the two methyl moieties under radical
conditions according to Yin and Tan[13b] was unsuccessful
(Scheme 2).
Scheme 4. Introduction of an ester moiety via 8a. Reagents and
conditions: (i) Diethyl 2-acetylaminomalonate, K2CO3, KI,
CH3CN, reflux; (ii) LiBr, H2O, DMF, reflux; (iii) POCl3, CH3CN,
reflux.
Scheme 2. Attempt at radical benzylic bromination of 4.
Bromides 6a[28] and 6b[29] were submitted to nucleophilic
Attempts to oxidize both methyl groups to either alde- substitution with commercially available diethyl 2-acetyl-
hyde or carboxylic acid groups with selenium dioxide[24] or aminomalonate. Ester decarboxylation was successfully ini-
potassium permanganate, respectively, were disappointing. tiated with compound 7a to afford amidoester 8a in excel-
Although the C1 methyl group was easily oxidized under lent yield. Considering the reported conditions,[10b,30]
mild conditions, the C3 alkyl group was completely unreac- Bischler–Napieralski cyclization was carried out in the pres-
tive. A few years ago, Janin et al. provided an indirect ence of phosphorus oxychloride. Unfortunately, in the case
method to oxidize the C3 position without using toxic sele- of 7a, the Robinson–Gabriel reaction was favored to afford
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F. Caillé, F. Buron, É. Tóth, F. Suzenet
FULL PAPER
exclusively oxazole 9a.[31] Therefore, the cyclization step was
carried out prior to ester decarboxylation (Scheme 5).
Bischler–Napieralski cyclization of compounds 7 in re-
fluxing phosphorus oxychloride afforded 4H-isoquinolines
10, which were submitted to Krapcho decarboxylation. The
use of a classical solvent such as DMF or DMSO[32] led to
isoquinolines 11 with poor and irreproducible yields. The
choice of pyridine as the solvent for the decarboxylation
created basic conditions, which promoted the in situ aroma-
tization of the formed dihydroisoquinoline. As a result, de-
sired products 11 were isolated in 75 and 64% yield, respec-
tively, reproducibly.
Scheme 7. Synthesis of isoquinoline ligands 16a and 16b. Reagents
and conditions: (i) HN(CH2CO2Et)2, K2CO3, KI, CH3CN, reflux;
(ii) LiOH, THF/H2O, room temp.; (iii) Dowex 1X2 100(Cl),
HCOOH.
Conclusions
To conclude, we have developed efficient routes to highly
substituted isoquinoline scaffolds from readily accessible
starting materials. We have overcome the lack of reactivity
of the challenging C3 position by introducing an ester func-
Scheme 5. Synthesis of isoquinolines 11a and 11b. Reagents and tion before isoquinoline ring formation. This approach al-
conditions: (i) POCl3, reflux; (ii) NaI, pyridine, reflux.
lows very easy access to a wide range of C1 and C3 poly-
substituted isoquinolines starting from three complemen-
tary synthons of type 12, 13, and 14. We have function-
alized 1,3-dibromomethylisoquinoline derivatives 14 to
build new ligands for lanthanide complexation. These li-
gands are currently being tested for lanthanide complex-
ation properties.
This sequence afforded the isoquinoline scaffold bearing
a reactive ester or methyl moiety at the C3 or C1 position,
respectively. As expected, these two positions can be easily
functionalized into different highly reactive groups
(Scheme 6).
Experimental Section
General Information: All solvents used were analytical grade. All
reactions were monitored by thin-layer chromatography, which was
performed on aluminum sheets covered with silica gel 60 F254. Vi-
sualization was realized by UV-light irradiation (254 and 365 nm)
or with a cerium molybdate stain. Purification by flash chromatog-
raphy was realized on silica gel 40–70 nm (230–400 mesh). Melting
Scheme 6. Functionalization of the C1 and C3 positions of 11a and
11b. Reagents and conditions: (i) SeO2, 1,4-dioxane, reflux;
(ii) NaBH4, EtOH, reflux; (iii) PBr3, CHCl3, reflux.
1
points were measured with a Kofler bench. H NMR (400 MHz)
and 13C NMR (100 MHz) were recorded with CDCl3 or CD3OD
as solvent and tetramethylsilane (TMS) as reference. Infrared
analysis were carried out on a diamond crystal (ATR-D). High-
resolution mass spectrometry was recorded at the Centre Régionale
de Mesure Physique, Clermont-Ferrand University, with the elec-
trospray ionization (ESI) technique. Mass spectroscopy (ESI) was
recorded with a Perkin–Elmer SCIEX AOI 300 spectrometer.
Oxidation of the C1 methyl in the presence of selenium
dioxide in refluxing 1,4-dioxane afforded aldehydes 12.
Among the variety of reactions that can be carried out over
the two carbonyl moieties,[33] reduction of both groups with
sodium borohydride in refluxing ethanol yielded diols 13.
These two highly reactive hydroxy functions can be submit-
ted to various reactions[34] such as bromination with phos-
phorus tribromide in refluxing chloroform to give com-
pounds 14. The highly reactive C1 and C3 electrophilic po-
tert-Butyl[1-(2,5-dimethoxyphenyl)-2-nitropropoxy]dimethylsilane
(2): To a solution of aldehyde 1 (1 g, 1 equiv.) in methanol (10 mL)
was added nitroethane (2.2 mL, 5 equiv.) and a catalytic amount of
P(nBu)3 (150 μL, 0.1 equiv.), and the resulting mixture was stirred
sitions of these bromomethylisoquinolines can react with a for 14 h at room temperature. The solvent was evaporated, and the
wide range of nucleophiles.[13b,21] As part of our research
resulting orange oil was purified by flash chromatography on silica
gel (petroleum ether/dichloromethane, 1:4) to give the aldol adduct
project, we functionalized these isoquinoline scaffolds to
(1.31 g, 90%) as a yellow solid. The crude product was used with-
synthesize ligands for lanthanide complexation (Scheme 7).
out further purification in the next step. To a solution of the aldol
Nucleophilic substitution at the C1 and C3 positions
adduct (1.31 g, 1 equiv.) in dichloromethane (30 mL) was added
with diethyl iminodiacetate in the presence of potassium
TBDMSCl (1.23 g, 1.5 equiv.) and imidazole (740 mg, 2 equiv.).
The resulting mixture was heated at reflux for 16 h, and after being
cooled to room temperature, the medium was hydrolyzed with
carbonate and potassium iodide in refluxing acetonitrile
gave tetraesters 15. Final saponification with lithium hy-
droxide followed by purification on Dowex ion-exchange
resin afforded desired isoquinoline ligands 16 in almost
quantitative yields.
water (10 mL), the organic phase was separated, and the aqueous
phase was extracted with dichloromethane (2ϫ10 mL). The com-
bined organic phases were dried with MgSO4, filtered, and concen-
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Efficient Access to C1- and C3-Functionalized Isoquinolines
trated. The crude oil was purified by flash chromatography on silica
gel (petroleum ether/ethyl acetate, 9:1) to give silyl ether 2 (1.9 g,
73 %) as a colorless oil of two diastereoisomers. 1H NMR
5,8-Dimethoxy-1,3-dimethylisoquinoline (4): To a solution of com-
pound 3 (150 mg, 1 equiv.) in toluene (5 mL) was added phospho-
rus oxychloride (380 μL, 10 equiv.), and the mixture was heated at
(400 MHz, CDCl3, 25 °C): δ (diastereoisomer 1) = 6.97 (m, 1 H, reflux for 5 h. After being cooled to 0 °C, the medium was hy-
ArH), 6.82 (m, 1 H, ArH), 6.79 (m, 1 H, ArH), 5.51 (d, J = 12 Hz,
1 H, CHOSi), 4.7 (m, 1 H, CHNO2), 3.81 (s, 3 H, OCH3), 3.77 (s,
drolyzed with a saturated solution of sodium hydrogencarbonate
(30 mL) to pH 8. The phases were separated, and the aqueous
3 H, OCH3), 1.27 (d, J = 8 Hz, 3 H, CH3), 0.8 (s, 9 H, 3 CH3), phase was extracted with ethyl acetate (10 mL). The combined or-
–0.01 (s, 3 H, SiCH3), –0.23 (s, 3 H, SiCH3) ppm. 1H NMR
ganic phases were dried with MgSO4, filtered, and concentrated.
(400 MHz, CDCl3, 25 °C): δ (diastereoisomer 2) = 7.05 (m, 1 H, The crude oil was purified by flash chromatography on silica gel
ArH), 6.82 (m, 1 H, ArH), 6.79 (m, 1 H, ArH), 5.80 (d, J = 4 Hz, (petroleum ether/ethyl acetate, 9:1) to give isoquinoline 4 (55 mg,
1 H, CHOSi), 4.76 (m, 1 H, CHNO2), 3.84 (s, 3 H, OCH3), 3.77 62 %) as pale yellow needles. M.p. 60 °C. 1H NMR (400 MHz,
(s, 3 H, OCH3), 1.31 (d, J = 8 Hz, 3 H, CH3), 0.91 (s, 9 H, 3 CDCl3, 25 °C): δ = 7.68 (s, 1 H, ArH), 6.83 (d, J = 8 Hz, 1 H,
CH3), 0.01 (s, 3 H, SiCH3), –0.11 (s, 3 H, SiCH3) ppm. 13C NMR ArH), 6.69 (d, J = 8 Hz, 1 H, ArH), 3.96 (s, 3 H, OCH3), 3.91 (s,
(100 MHz, CDCl3, 25 °C): δ (diastereoisomer 1) = 153.5 (CIV), 3 H, OCH3), 3.07 (s, 3 H, CH3), 2.63 (s, 3 H, CH3) ppm. 13C NMR
150.5 (CIV), 128.6 (CIV), 114.7 (ArCH), 113.2 (ArCH), 111.6 (100 MHz, CDCl3, 25 °C): δ = 157.7 (CIV), 152.2 (CIV), 150.7 (CIV),
(ArCH), 89.7 (CHNO2), 69.8 (CHOSi), 55.8 (OCH3), 55.6 (OCH3), 148.3 (CIV), 131.6 (CIV), 119.0 (CIV), 111.1 (ArCH), 107.6 (ArCH),
25.4 (3 CH3), 17.9 (CIV), 15.3 (CH3), –5.1 (CH3Si), –5.9 104.6 (ArCH), 56.1 (OCH3), 55.8 (OCH3), 28.7 (ArCH3), 24.5
(CH3Si) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ (diastereoiso-
(ArCH ) ppm. IR (ATR-D): ν = 2931, 1574, 1260, 1242, 1093,
˜
3
mer 2) = 153.7 (CIV), 149.3 (CIV), 128.9 (CIV), 114.7 (ArCH), 113.6
1048, 730 cm–1. HRMS (ESI): calcd. for C13H16NO2 [M + H]+
(ArCH), 110.9 (ArCH), 84.8 (CHNO2), 70.5 (CHOSi), 55.6 218.1181; found 218.1178.
(OCH3), 55.6 (OCH3), 25.6 (3 CH3), 17.9 (CIV), 10.3 (CH3), –4.9
5,8-Dimethoxy-3-methylisoquinoline-1-carbaldehyde (4a): To a solu-
(CH Si), –5.9 (CH Si) ppm. IR (ATR-D): ν = 2930, 1551, 1498,
˜
3
3
tion of compound 4 (300 mg, 1 equiv.) in 1,4-dioxane (10 mL) was
added selenium dioxide (300 mg, 2 equiv.), and the mixture was
heated at reflux for 1 h. After being cooled to room temperature,
the solution was filtered through a pad of Celite, the solvent was
evaporated, and the residue was dissolved in ethyl acetate (10 mL).
The organic phase was then washed with water (10 mL), dried with
MgSO4, filtered, and concentrated. The crude product was purified
by flash chromatography on silica gel (petroleum ether/ethyl acet-
ate, 1:1) to give the aldehyde (220 mg, 70%) as a yellow powder.
1389, 1215, 1046, 836, 778 cm–1. HRMS (ESI): calcd. for
C17H29NO5NaSi [M + Na]+ 378.1713; found 378.1714.
N-[1-(tert-Butyldimethylsilyloxy)-1-(2,5-dimethoxyphenyl)propan-
2-yl]acetamide (3): To a solution of compound 2 (250 mg, 1 equiv.)
in a mixture of methanol/ammoniac (99:1, 10 mL) was added
Raney nickel (25 mg, 10%). The flask was placed under a hydrogen
atmosphere (1 atm), and the mixture was vigorously stirred at 50 °C
for 3 h. After being cooled, the medium was filtered through a pad
of Celite, and the filtrate was evaporated to yield the crude amine
as a colorless oil. This amine was directly used without further
purification in the next step. To a solution of the crude amine
(150 mg, 1 equiv.) in dichloromethane (10 mL) was added pyridine
(190 μL, 5 equiv.) and acetic anhydride (870 μL, 20 equiv.), and the
mixture was stirred for 3 h at room temperature. The organic phase
was then washed with water (5 mL), dried with MgSO4, filtered,
and concentrated. The crude oil was purified by flash chromatog-
raphy on silica gel (ethyl acetate) to give intermediate 3 (150 mg,
69% over two steps) as a white powder of two diastereoisomers.
M.p. 82 °C. 1H NMR (400 MHz, CDCl3, 25 °C): δ (diastereoiso-
mer 1) = 6.93 (m, 1 H, ArH), 6.74 (m, 1 H, ArH), 6.72 (m, 1 H,
ArH), 5.73 (br., 1 H, NH), 5.02 (d, J = 4 Hz, 1 H, CHOSi), 4.15
1
M.p. 100 °C. H NMR (400 MHz, CDCl3, 25 °C): δ = 10.85 (s, 1
H, CHO), 7.98 (s, 1 H, ArH), 6.89 (d, J = 8 Hz, 1 H, ArH), 6.79
(d, J = 8 Hz, 1 H, ArH), 3.97 (s, 3 H, OCH3), 3.96 (s, 3 H, OCH3),
2.76 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
194.1 (CHO), 153.1 (CIV), 152.3 (CIV), 149.8 (CIV), 148.6 (CIV),
131.6 (CIV), 118.2 (CIV), 115.9 (ArCH), 107.7 (ArCH), 105.4
(ArCH), 56.1 (OCH3), 56.0 (OCH3), 24.4 (ArCH3) ppm. IR (ATR-
D): ν = 2929, 1693, 1239, 1097, 804, 727 cm–1. HRMS (ESI): calcd.
˜
for C14H18NO4 [M + H + CH3OH]+ 264.1236; found 264.1227.
(5,8-Dimethoxy-3-methylisoquinolin-1-yl)methyl Acetate (4b): To a
solution of aldehyde (200 mg, 1 equiv.) in methanol (10 mL) was
added sodium borohydride (50 mg, 2 equiv.) in portions, and the
mixture was stirred for 3 h at room temperature. The medium was
(m, 1 H, CHN), 3.8 (s, 3 H, OCH3), 3.74 (s, 3 H, OCH3), 1.83 (s, then hydrolyzed with water (10 mL), and the solvent was evapo-
3 H, COCH3), 0.95 (m, 12 H, CH3, 3 CH3), 0.06 (s, 3 H, SiCH3), rated. The residue was dissolved in ethyl acetate (10 mL) and
1
–0.13 (s, 3 H, SiCH3) ppm. H NMR (400 MHz, CDCl3, 25 °C): δ washed with water (5 mL). The organic phase was dried with
(diastereoisomer 2) = 7.01 (m, 1 H, ArH), 6.74 (m, 1 H, ArH), 6.72
(m, 1 H, ArH), 5.73 (br., 1 H, NH), 5.07 (d, J = 4 Hz, 1 H, CHOSi),
MgSO4, filtered, and concentrated to yield a crude alcohol
(180 mg, 90%) as a white solid. This compound was used without
4.25 (m, 1 H, CHN), 3.78 (s, 3 H, OCH3), 3.75 (s, 3 H, OCH3), further purification in the next step. To a solution of the crude
1.93 (s, 3 H, COCH3), 1.2 (d, J = 4 Hz, 3 H, CH3), 0.95 (m, 9 H,
alcohol (170 mg, 1 equiv.) in THF (10 mL) was successively added
3 CH3), 0.08 (s, 3 H, SiCH3), –0.11 (s, 3 H, SiCH3) ppm. 13C NMR pyridine (720 μL, 12 equiv.), acetic anhydride (700 μL, 10 equiv.),
(100 MHz, CDCl3, 25 °C): δ (diastereoisomer 1) = 169.0 (C=O), and a catalytic amount of DMAP. The mixture was stirred at room
153.6 (CIV), 150.1 (CIV), 131.3 (CIV), 113.6 (ArCH), 113.1 (ArCH),
111.1 (ArCH), 70.8 (CHOSi), 56.0 (OCH3), 55.9 (OCH3), 49.8
temperature for 24 h, and the solvent was evaporated. The crude
product was purified by flash chromatography on silica gel (petro-
(CHN), 26.1 (3 CH3), 26.1 (CIV), 23.6 (COCH3), 18.6 (CH3), –4.5 leum ether/ethyl acetate, 1:1) to give the ester (120 mg, 60%) as a
(CH3Si), –5.0 (CH3Si) ppm. 13C NMR (100 MHz, CDCl3, 25 °C):
pale yellow solid. M.p. 109 °C. 1H NMR (400 MHz, CDCl3,
25 °C): δ = 7.80 (s, 1 H, ArH), 6.86 (d, J = 8 Hz, 1 H, ArH), 6.72
δ (diastereoisomer 2) = 169.0 (C=O), 153.4 (CIV), 150.1 (CIV), 131.3
(CIV), 113.5 (ArCH), 112.6 (ArCH), 111.1 (ArCH), 71.2 (CHOSi), (d, J = 8 Hz, 1 H, ArH), 5.79 (s, 2 H, CH2O), 3.94 (s, 3 H, OCH3),
56.0 (OCH3), 55.9 (OCH3), 49.4 (CHN), 26.1 (3 CH3), 26.1 (CIV),
3.90 (s, 3 H, OCH3), 2.66 (s, 3 H, CH3), 2.18 (s, 3 H, COCH3) ppm.
23.8 (COCH3), 18.5 (CH3), –4.4 (CH3Si), –4.9 (CH3Si) ppm. IR 13C NMR (100 MHz, CDCl3, 25 °C): δ = 171.3 (C=O), 153.0 (CIV),
(ATR-D): ν = 3269, 2953, 1642, 1498, 1214, 1044, 862, 776 cm–1.
151.0 (CIV), 150.9 (CIV), 148.4 (CIV), 131.9 (CIV), 118.1 (CIV), 113.1
(ArCH), 107.6 (ArCH), 104.8 (ArCH), 68.9 (CH2O), 56.1 (OCH3),
˜
HRMS (ESI): calcd. for C19H33NO4NaSi [M + Na]+ 390.2077;
found 390.2068.
55.8 (OCH ), 24.5 (ArCH ), 21.3 (COCH ) ppm. IR (ATR-D): ν
˜
3
3
3
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= 2942, 1735, 1235, 1028, 814 cm–1. HRMS (ESI): calcd. for
filtered, and concentrated. The crude oil was purified by flash
chromatography on silica gel (petroleum ether/ethyl acetate, 6:4) to
give compound 8a (360 mg, 93 %) as a pale yellow solid. M.p.
73 °C. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 6.73 (m, 2 H, ArH),
6.66 (m, 1 H, ArH), 6.34 (br., 1 H, NH), 4.70 (m, 1 H, CH), 4.14
(m, 2 H, CO2CH2), 3.78 (s, 3 H, OCH3), 3.73 (s, 3 H, OCH3), 3.05
(m, 2 H, ArCH2 ), 1.92 (s, 3 H, COCH3 ), 1.25 (m, 3 H,
CO2CH2CH3) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
172.1 (C=O), 170.0 (C=O), 153.8 (CIV), 151.9 (CIV), 126.0 (CIV),
117.4 (ArCH), 113.0 (ArCH), 111.7 (ArCH), 61.4 (CO2CH2), 55.9
(OCH3), 53.5 (OCH3), 41.6 (CHN), 32.7 (ArCH2), 23.2 (COCH3),
C15H18NO4 [M + H]+ 276.1236; found 276.1235.
1-(Acetoxymethyl)-5,8-dimethoxy-3-methylisoquinoline 2-Oxide (5):
To a solution of the ester (100 mg, 1 equiv.) in dichloromethane
(10 mL) was added m-CPBA (190 mg, 3 equiv.), and the mixture
was stirred at room temperature for 14 h. The medium was washed
successively with a solution of sodium hydroxide (1 m, 10 mL) and
water (10 mL). The organic phase was dried with MgSO4, filtered,
and concentrated to afford isoquinoline N-oxide 5 (105 mg, quanti-
tative) as a brown oil. 1H NMR (400 MHz, CDCl3, 25 °C): δ =
8.07 (s, 1 H, ArH), 6.8 (m, 2 H, ArH), 6.12 (s, 2 H, CH2O), 3.95
(s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 2.65 (s, 3 H, CH3), 2.11 (s, 3
H, COCH3) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 171.2
(C=O), 157.4 (CIV), 148.4 (CIV), 145.7 (CIV), 138.5 (CIV), 122.2
(CIV), 121.6 (CIV), 118.4 (ArCH), 108.1 (ArCH), 106.4 (ArCH),
60.0 (CH2O), 56.2 (OCH3), 56.1 (OCH3), 21.2 (COCH3), 18.8
14.3 (CO CH CH ) ppm. IR (ATR-D): ν = 3286, 2935, 1737, 1654,
˜
2
2
3
1501, 1224, 1042, 1025 cm– 1 . HRMS (ESI): calcd. for
C15H21NO5Na [M + Na]+ 318.1317; found 318.1323.
4-(2,5-Dimethoxybenzyl)-5-ethoxy-2-methyloxazole (9a): To a solu-
tion of compound 8a (100 mg, 1 equiv.) in chloroform (10 mL) was
added phosphorus oxychloride (0.4 mL, 10 equiv.), and the mixture
was heated at reflux for 2 h. After being cooled to 0 °C, the solution
was hydrolyzed with a saturated solution of sodium hydrogencar-
bonate (30 mL) until pH 8. The phases were separated, and the
aqueous one was extracted with dichloromethane (10 mL). The
combined organic phases were dried with MgSO4, filtered, and
concentrated. The crude oil was purified by flash chromatography
on silica gel (petroleum ether/ethyl acetate, 1:1) to give oxazole 9a
(60 mg, 64%) as a yellow oil. 1H NMR (400 MHz, CDCl3, 25 °C):
δ = 6.75 (m, 2 H, ArH), 6.68 (m, 1 H, ArH), 4.05 (m, 2 H, OCH2),
3.78 (s, 3 H, OCH3), 3.73 (s, 3 H, OCH3), 3.69 (s, 2 H, ArCH2), 2.31
(s, 3 H, CH3), 1.29 (m, 3 H, OCH2CH3) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 154.5 (CIV), 153.8 (CIV), 152.6 (CIV) 151.9
(CIV), 129.2 (CIV), 116.6 (ArCH), 115.2 (CIV), 111.5 (ArCH), 111.5
(CHOEt), 70.6 (OCH2), 56.3 (OCH3), 55.9 (OCH3), 25.1 (ArCH2),
(ArCH ) ppm. IR (ATR-D): ν = 2941, 1732, 1230, 1026, 730 cm–1.
˜
3
HRMS (ESI): calcd. for C15H17NO5Na [M + Na]+ 314.1004; found
314.0995.
Diethyl 2-Acetylamido-2-(2,5-dimethoxybenzyl)malonate (7a): To a
solution of bromide 6a[28] (12 g, 1 equiv.) in acetonitrile (500 mL)
was successively added diethyl 2-acetylaminomalonate (12.3 g,
1.1 equiv.), potassium carbonate (13.9 g, 2 equiv.), and potassium
iodide (8.6 g, 1 equiv.). The mixture was heated at reflux for 14 h,
and after being cooled to room temperature, the solvent was evapo-
rated. The residue was dissolved in dichloromethane (200 mL), and
the organic phase was washed with water (100 mL), dried with
MgSO4, filtered, and concentrated. The crude oil was purified by
flash chromatography on silica gel (petroleum ether/ethyl acetate,
7:3) to give compound 7a (16.7 g, 88 %) as a white solid. M.p.
85 °C. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 6.72 (m, 2 H, ArH),
6.56 (m, 1 H, ArH), 6.48 (br., 1 H, NH), 4.25 (m, 4 H, CO2CH2),
3.70 (s, 3 H, OCH3), 3.67 (s, 3 H, OCH3), 3.63 (s, 2 H, ArCH2),
1.94 (s, 3 H, COCH3), 1.29 (m, 6 H, CO2CH2CH3) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 169.1 (C=O), 168.1 (C=O), 166.6
(C=O), 153.5 (CIV), 152.4 (CIV), 125.0 (CIV), 118.3 (ArCH), 113.2
(ArCH), 111.5 (ArCH), 66.4 (CIV), 62.6 (CO2CH2), 62.5
(CO2CH2), 56.1 (OCH3), 55.8 (OCH3), 33.1 (ArCH2), 23.1
(COCH3), 14.2 (CO2CH2CH3), 14.1 (CO2CH2CH3) ppm. IR
15.2 (ArCH ), 14.6 (COCH ) ppm. IR (ATR-D): ν = 2937, 1669,
˜
3
3
1498, 1218, 1024 cm–1. MS (ESI): m/z = 278 [M + H]+. Oxazole 9a
decomposes even when it is kept under an atmosphere of argon at
–20 °C.
Diethyl 5,8-Dimethoxy-1-methylisoquinoline-3,3(4H)-dicarboxylate
(10a): A solution of compound 7a (14 g) in phosphorus oxychlor-
ide (250 mL) was heated at reflux for 2 h, and after being cooled
to room temperature, the solvent was evaporated. The residue was
hydrolyzed at 0 °C with a saturated solution of sodium hydrogen-
carbonate (1 L) to pH 8, and the aqueous phase was extracted with
ethyl acetate (2 ϫ 100 mL). The organic phase was dried with
MgSO4, filtered, and concentrated. The crude solid was purified by
flash chromatography on silica gel (petroleum ether/ethyl, 6:4) to
give compound 10a (10.9 g, 82%) as a white solid. M.p. 112 °C. 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 6.91 (d, J = 8 Hz, 1 H, ArH),
6.78 (d, J = 8 Hz, 1 H, ArH), 4.2 (m, 4 H, CO2CH2), 3.81 (s, 3 H,
OCH3), 3.80 (s, 3 H, OCH3), 3.25 (s, 2 H, ArCH2), 2.58 (s, 3 H,
CH3), 1.18 (m, 6 H, CO2CH2CH3) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 169.7 (2 C=O), 167.9 (CIV), 152.1 (CIV), 150.3
(CIV), 125.2 (CIV), 120.1 (CIV), 114.7 (ArCH), 110.9 (ArCH), 69.9
(CIV), 62.1 (2 CO2CH2), 56.5 (OCH3), 56.2 (OCH3), 28.1
(N=CCH3), 26.0 (ArCH2), 14.2 (2 CO2CH2CH3) ppm. IR (ATR-
(ATR-D): ν = 3255, 2985, 1740, 1639, 1219, 1039 cm–1. HRMS
˜
(ESI): calcd. for C18H26NO7 [M + H]+ 368.1709; found 368.1709.
Diethyl 2-Acetylamido-2-(3,4-dimethoxybenzyl)malonate (7b): Same
procedure as for compound 7a starting from bromide 6b.[29] Yield:
75 %. White solid. M.p. 100 °C. 1H NMR (400 MHz, CDCl3,
25 °C): δ = 6.74 (d, J = 8 Hz, 1 H, ArH), 6.52 (m, 3 H, 2 ArH,
NH), 4.26 (m, 4 H, CO2CH2), 3.83 (s, 3 H, OCH3), 3.79 (s, 3 H,
OCH3), 3.58 (s, 2 H, ArCH2), 2.01 (s, 3 H, COCH3), 1.28 (t, J =
8 Hz, 6 H, CO2CH2CH3) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 169.1 (C=O), 167.7 (C=O), 148.8 (CIV), 148.4 (CIV),
127.8 (CIV), 122.1 (ArCH), 113.3 (ArCH), 111.2 (ArCH), 67.5
(CIV), 62.8 (2 CO2CH2), 56.0 (OCH3), 55.9 (OCH3), 37.6 (ArCH2),
23.3 (COCH ), 14.2 (2 CO CH CH ) ppm. IR (ATR-D): ν = 3279,
˜
3
2
2
3
2979, 1744, 1646, 1513, 1257, 1238, 1188, 1157, 1136, 1027 cm–1.
HRMS (ESI): calcd. for C18H25NO7Na [M + Na]+ 390.1529; found
390.1538.
D): ν = 2992, 1733, 1272, 1239, 1099, 1059 cm–1. HRMS (ESI):
˜
calcd. for C18H24NO6 [M + H]+ 350.1604; found 350.1588.
Ethyl 2-Acetamido-3-(2,5-dimethoxyphenyl)propanoate (8a): To a
solution of compound 7a (480 mg, 1 equiv.) in DMF (10 mL) was
added lithium bromide (125 mg, 1.1 equiv.) and water (52 μL,
2.2 equiv.), and the mixture was heated at reflux for 16 h. After
being cooled to room temperature, the residue was dissolved in
dichloromethane (10 mL). The organic phase was washed with a
saturated solution of sodium chloride (10 mL), dried with MgSO4,
Diethyl 6,7-Dimethoxy-1-methylisoquinoline-3,3(4H)-dicarboxylate
(10b): Same procedure as for compound 10a starting from 7b.
Yield: 57%. White solid. M.p. 107 °C. 1H NMR (400 MHz, CDCl3,
25 °C): δ = 7.00 (s, 1 H, ArH), 6.70 (s, 1 H, ArH), 4.21 (m, 4 H,
CO2CH2), 3.91 (s, 3 H, OCH3), 3.90 (s, 3 H, OCH3), 3.28 (s, 2 H,
A r C H 2 ) , 2 . 5 0 ( s, 3 H , C H 3 ) , 1 . 2 2 ( t , J = 8 H z , 6 H ,
CO2CH2CH3) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
2124
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2120–2127

Efficient Access to C1- and C3-Functionalized Isoquinolines
169.8 (2 C=O), 167.3 (CIV), 151.9 (CIV), 148.1 (CIV), 127.8 (CIV), 1135, 1111, 991, 881 cm–1. HRMS (ESI): calcd. for C15H15NO5Na
122.1 (CIV), 110.6 (ArCH), 109.2 (ArCH), 70.4 (CIV), 62.3 (2
[M + Na]+ 312.0848; found 312.0844.
CO2CH2), 56.4 (OCH3), 56.2 (OCH3), 31.5 (ArCH2), 23.9
(5,8-Dimethoxyisoquinoline-1,3-diyl)dimethanol (13a): To a solution
of aldehyde 12a (1.5 g, 1 equiv.) in ethanol (100 mL) was added
sodium borohydride (800 mg, 4 equiv.), and the mixture was heated
at reflux for 3 h. After being cooled to room temperature, the sol-
vent was evaporated, and the residue was dissolved in dichloro-
methane (50 mL). The organic phase was washed with water
(20 mL), dried with MgSO4, filtered, and concentrated to yield
(ArCH ), 14.2 (2 CO CH CH ) ppm. IR (ATR-D): ν = 2986, 1734,
˜
3
2
2
3
1300, 1267, 1161, 1062 cm–1. HRMS (ESI): calcd. for C18H24NO6
[M + H]+ 350.1604; found 350.1588.
Ethyl 5,8-Dimethoxy-1-methylisoquinoline-3-carboxylate (11a): To a
solution of compound 10a (5.5 g, 1 equiv.) in pyridine (250 mL)
was added sodium iodide (6.7 g, 3 equiv.), and the mixture was
heated at reflux for 24 h. After being cooled to room temperature,
the solvent was evaporated, and the residue was dissolved in ethyl
1
pure diol 13a (950 mg, 72%) as a yellow powder. M.p. 124 °C. H
NMR (400 MHz, CDCl3, 25 °C): δ = 7.95 (s, 1 H, ArH), 6.91 (d,
acetate (100 mL). The organic phase was washed with brine J = 8 Hz, 1 H, ArH), 6.76 (d, J = 8 Hz, 1 H, ArH), 5.25 (s, 2 H,
(50 mL), dried with MgSO4, filtered, and concentrated. The crude
solid was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate, 5:5) to give isoquinoline 11a (3.1 g, 75%) as a
CH2OH), 4.89 (s, 2 H, CH2OH), 3.95 (s, 3 H, OCH3), 3.92 (s, 3 H,
OCH3), 3.75 (br., 2 H, OH) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 158.0 (CIV), 151.6 (CIV), 150.8 (CIV), 148.7 (CIV), 131.2
(CIV), 118.0 (CIV), 110.7 (ArCH), 108.5 (ArCH), 105.6 (ArCH),
1
yellow solid. M.p. 85 °C. H NMR (400 MHz, CDCl3, 25 °C): δ =
8.72 (s, 1 H, ArH), 6.91 (m, 2 H, ArH), 4.49 (q, J = 8 Hz, 2 H, 65.6 (CH2OH), 65.1 (CH2OH), 56.1 (OCH3), 55.9 (OCH3) ppm.
CO2CH2), 3.96 (s, 3 H, OCH3), 3.92 (s, 3 H, OCH3), 3.15 (s, 3 H, IR (ATR-D): ν = 3397, 3199, 2944, 1332, 1261, 1233, 1094, 1022,
˜
CH3), 1.45 (t, J = 8 Hz, 3 H, CO2CH2CH3) ppm. 13C NMR 804 cm–1. HRMS (ESI): calcd. for C13H16NO4 [M + H]+ 250.1079;
(100 MHz, CDCl3, 25 °C): δ = 166.2 (C=O), 159.1 (CIV), 151.8 found 250.1071.
(CIV), 149.5 (CIV), 140.6 (CIV), 130.2 (CIV), 121.9 (CIV), 116.7
(6,7-Dimethoxyisoquinoline-1,3-diyl)dimethanol (13b): Same pro-
(ArCH), 108.6 (ArCH), 108.5 (ArCH), 61.8 (CO2CH2), 56.1
cedure of reduction as for compound 13a starting from compound
(OCH3), 56.0 (OCH3), 29.1 (ArCH3), 14.6 (CO2CH2CH3) ppm. IR
12b. Yield: 65%. White solid. M.p. 89 °C. 1H NMR (400 MHz,
(ATR-D): ν = 2936, 1718, 1259, 1045, 1030, 728 cm–1. HRMS
˜
CDCl3, 25 °C): δ = 7.49 (s, 1 H, ArH), 7.09 (s, 1 H, ArH), 7.04 (s,
1 H, ArH), 5.13 (s, 2 H, CH2OH), 4.88 (s, 2 H, CH2OH), 4.03 (s, 3
(ESI): calcd. for C15H18NO4 [M + H]+ 276.1236; found 276.1230.
Ethyl 6,7-Dimethoxy-1-methylisoquinoline-3-carboxylate (11b): H, OCH3), 4.03 (s, 3 H, OCH3) ppm. 13C NMR (100 MHz, CDCl3,
Same procedure as for compound 11a starting from 10b. Yield:
64 %. Yellow solid. M.p. 150 °C. 1H NMR (400 MHz, CDCl3, (CIV), 120.1 (CIV), 115.8 (ArCH), 105.7 (ArCH), 101.5 (ArCH),
25 °C): δ = 8.30 (s, 1 H, ArH), 7.31 (s, 1 H, ArH), 7.17 (s, 1 H, 65.5 (CH2OH), 61.7 (CH2OH), 56.3 (2 OCH3) ppm. IR (ATR-D):
25 °C): δ = 154.9 (CIV), 153.4 (CIV), 150.5 (CIV), 149.9 (CIV), 133.8
ArH), 4.48 (q, J = 8 Hz, 2 H, CO2CH2), 4.05 (s, 3 H, OCH3), ν = 3389, 3133, 1462, 1246, 1077, 876 cm–1. HRMS (ESI): calcd.
˜
4.02 (s, 3 H, OCH3), 2.95 (s, 3 H, CH3), 1.44 (t, J = 8 Hz, 3 H,
CO2CH2CH3) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
166.5 (C=O), 156.7 (CIV), 153.1 (CIV), 151.8 (CIV), 140.0 (CIV),
132.4 (CIV), 125.3 (CIV), 121.9 (ArCH), 106.8 (ArCH), 104.2
(ArCH), 61.8 (CO2CH2), 56.4 (OCH3), 56.3 (OCH3), 23.1
for C13H16NO4 [M + H]+ 250.1079; found 250.1076.
1,3-Bis(bromomethyl)-5,8-dimethoxyisoquinoline (14a): To a solu-
tion of diol 13a (840 mg, 1 equiv.) in chloroform (100 mL) was
added phosphorus tribromide (1.9 mL, 6 equiv.), and the mixture
was heated at reflux for 14 h. After being cooled to 0 °C, the me-
dium was hydrolyzed with a saturated solution of sodium hydro-
gencarbonate (250 mL) to pH 8. The phases were separated, and
the aqueous phase was extracted with dichloromethane (100 mL).
(ArCH ), 14.7 (CO CH CH ) ppm. IR (ATR-D): ν = 2971, 1701,
˜
3
2
2
3
1509, 1426, 1249, 1217, 1160, 859 cm–1. HRMS (ESI): calcd. for
C15H18NO4 [M + H]+ 276.1236; found 276.1230.
Ethyl 1-Formyl-5,8-dimethoxyisoquinoline-3-carboxylate (12a): The combined organic phases were dried with MgSO4, filtered, and
Same procedure of oxidation as for compound 5 starting from 11a.
Yield: 67 %. Yellow powder. M.p. 113 °C. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 10.78 (s, 1 H, CHO), 8.99 (s, 1 H, ArH), 7.03
(s, 2 H, ArH), 4.52 (q, J = 8 Hz, 2 H, CO2CH2), 4.02 (s, 3 H,
O C H 3 ) , 3 . 9 9 ( s, 3 H , O C H 3 ) , 1 . 4 7 ( t , J = 8 Hz , 3 H,
concentrated. The crude oil was purified by flash chromatography
on silica gel (petroleum ether/ethyl acetate, 4:1) to give compound
14a (690 mg, 61 %) as a yellow solid. M.p. 150 °C. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 8.11 (s, 1 H, ArH), 6.94 (d, J = 8 Hz,
1 H, ArH), 6.89 (d, J = 8 Hz, 1 H, ArH), 5.28 (s, 2 H, CH2Br), 4.70
CO2CH2CH3) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = (s, 2 H, CH2Br), 4.02 (s, 3 H, OCH3), 3.96 (s, 3 H, OCH3) ppm.
192.7 (CHO), 165.5 (C=O), 154.6 (CIV), 154.4 (CIV), 149.7 (CIV),
13C NMR (100 MHz, CDCl3, 25 °C): δ = 155.7 (CIV), 150.7 (CIV),
141.9 (CIV), 130.5 (CIV), 124.2 (CIV), 120.4 (ArCH), 109.4 (ArCH),
149.4 (CIV), 149.0 (CIV), 131.9 (CIV), 118.7 (CIV), 115.3 (ArCH),
109.3 (ArCH), 62.3 (CO2CH2), 56.5 (OCH3), 56.3 (OCH3), 14.6 108.4 (ArCH), 107.6 (ArCH), 56.4 (OCH3), 56.1 (OCH3), 37.5
(CO CH CH ) ppm. IR (ATR-D): ν = 2931, 1736, 1695, 1259,
(CH Br), 34.7 (CH Br) ppm. IR (ATR-D): ν = 2927, 1251, 1089,
˜
2 2
˜
2
2
3
1026, 808 cm–1. HRMS (ESI): calcd. for C15H16NO5 [M + H]+
1036, 814, 724 cm–1. HRMS (ESI): calcd. for C13H14NO2Br2 [M +
H]+ 373.9391; found 373.9385.
290.1028; found 290.1024.
Ethyl 1-Formyl-6,7-dimethoxyisoquinoline-3-carboxylate (12b): 1,3-Bis(bromomethyl)-6,7-dimethoxyisoquinoline (14b): Same pro-
Same procedure of oxidation as for compound 5 starting from 11b.
Yield: 87 %. Yellow powder. M.p. 94 °C. 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 10.46 (s, 1 H, CHO), 8.81 (s, 1 H, ArH), 8.62
(s, 1 H, ArH), 7.27 (s, 1 H, ArH), 4.56 (q, J = 8 Hz, 2 H, CO2CH2),
cedure as for compound 14a starting from 13b. Yield: 70%. Yellow
solid. M.p. 196 °C. H NMR (400 MHz, CDCl3, 25 °C): δ = 7.63
(s, 1 H, ArH), 7.42 (s, 1 H, ArH), 7.08 (s, 1 H, ArH), 4.97 (s, 2 H,
CH2Br), 4.69 (s, 2 H, CH2Br), 4.08 (s, 2 H, OCH3), 4.03 (s, 3 H,
1
4.18 (s, 3 H, OCH3), 4.08 (s, 3 H, OCH3), 1.51 (t, J = 8 Hz, 3 H, OCH3) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 153.6 (CIV),
CO2CH2CH3) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 153.5 (CIV), 151.0 (CIV), 148.3 (CIV), 134.5 (CIV), 122.1 (CIV), 120.2
196.3 (CHO), 165.4 (C=O), 154.7 (CIV), 153.8 (CIV), 147.2 (CIV),
140.6 (CIV), 134.6 (CIV), 126.7 (ArCH), 124.7 (CIV), 106.1 (ArCH),
(ArCH), 105.7 (ArCH), 103.7 (ArCH), 56.4 (2 OCH3), 34.9
(CH Br), 32.3 (CH Br) ppm. IR (ATR-D): ν = 1509, 1429, 1259,
˜
2
2
104.1 (ArCH), 62.2 (CO2CH2), 56.7 (OCH3), 56.4 (OCH3), 14.6 842 cm–1. HRMS (ESI): calcd. for C13H14NO2Br2 [M + H]+
(CO CH CH ) ppm. IR (ATR-D): ν = 1726, 1694, 1504, 1263,
373.9391; found 373.9377.
˜
2
2
3
Eur. J. Org. Chem. 2011, 2120–2127
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2125

F. Caillé, F. Buron, É. Tóth, F. Suzenet
FULL PAPER
Tetraethyl 2,2,2ЈЈ,2ЈЈЈ-(5,8-dimethoxyisoquinoline-1,3-diyl)bis(me-
thylene)bis(azanetriyl)tetraacetate (15a): To a solution of com-
pound 14a (650 mg, 1 equiv.) in acetonitrile (70 mL) was success-
ively added diethyl iminodiacetate (720 mg, 2.2 equiv.), potassium
carbonate (930 mg, 4 equiv.), and potassium iodide (570 mg,
2 equiv.). The mixture was heated at reflux for 14 h, and after being
cooled to room temperature, the solvent was evaporated. The resi-
due was dissolved in dichloromethane (50 mL), and the organic
phase was washed with water (20 mL), dried with MgSO4, filtered,
and concentrated. The crude oil was purified by flash chromatog-
raphy on silica gel (ethyl acetate) to give tetraester 15a (1 g, 74%)
16a starting from 15b. Yield: 98%. Pale yellow solid. M.p. 140 °C.
1H NMR (400 MHz, CD3OD, 25 °C): δ = 7.86 (s, 1 H, ArH), 7.60
(s, 1 H, ArH), 7.44 (s, 1 H, ArH), 4.38 (s, 2 H, ArCH2), 4.03 (s, 6
H, OCH3), 3.80 (s, 4 H, NCH2), 3.73 (s, 4 H, NCH2), 3.65 (s, 2 H,
ArCH2) ppm. 13C NMR (100 MHz, CD3OD, 25 °C): δ = 174.2–
174.0 (4 C=O), 170.4 (CIV), 158.1 (CIV), 153.8 (CIV), 142.2 (CIV),
137.7 (CIV), 121.8 (CIV), 112.5 (ArCH), 107.1 (ArCH), 106.7
(ArCH), 57.7–56.8 (2 ArCH2, 4 CH2N, 2 OCH3) ppm. IR (ATR-
D): ν = 3000, 1715, 1613, 1506, 1258, 1162, 991, 866 cm–1. HRMS
˜
(ESI): calcd. for C21H24N3O10 [M – H]– 478.1462; found 478.1465.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H NMR and 13C NMR spectra for all isolated
compounds.
1
as a yellow oil. H NMR (400 MHz, CDCl3, 25 °C): δ = 8.06 (s, 1
H, ArH), 6.85 (d, J = 8 Hz, 1 H, ArH), 6.75 (d, J = 8 Hz, 1 H,
ArH), 4.80 (s, 2 H, ArCH2), 4.14 (m, 10 H, ArCH2, CO2CH2), 3.93
(s, 3 H, OCH3), 3.91 (s, 3 H, OCH3), 3.80 (s, 4 H, NCH2), 3.67 (s,
4 H, NCH2), 1.26 (t, J = 8 Hz, 6 H, CO2CH2CH3), 1.22 (t, J =
8 Hz, 6 H, CO2CH2CH3) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 172.3 (2 C=O), 171.4 (2 C=O), 157.0 (CIV), 151.3 (CIV),
148.9 (CIV), 140.3 (CIV), 131.8 (CIV), 122.0 (CIV), 112.4 (ArCH),
107.5 (ArCH), 107.1 (ArCH), 61.1–60.3 (4 CO2CH2, ArCH2),
56.0–55.2 (2 OCH3, ArCH2, 8 NCH2), 14.4 (4 CO2CH2CH3) ppm.
Acknowledgments
The authors thank the financial support of the Institut National
du Cancer, the Ligue contre le Cancer, and the French Research
Ministry (FC).
IR (ATR-D): ν = 2980, 1732, 1186, 1149, 1029, 808 cm–1. HRMS
˜
(ESI): calcd. for C29H42N3O10 [M + H]+ 592.2870; found 592.2859.
[1] K. W. Bentley in The Isoquinoline Alkaloids, Hardwood Aca-
demic, Amsterdam 1998, vol. 1.
Tetraethyl 2,2,2ЈЈ,2ЈЈЈ-(6,7-dimethoxyisoquinoline-1,3-diyl)bis(meth-
ylene)bis(azanetriyl)tetraacetate (15b): Same procedure as for com-
pound 15a starting from 14b. Yield: 77%. Yellow oil. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 8.37 (s, 1 H, ArH), 7.69 (s, 1 H,
ArH), 7.05 (s, 1 H, ArH), 4.40 (s, 2 H, ArCH2), 4.19–4.13 (m, 11
H, CO2CH2, OCH3), 4.01 (s, 3 H, OCH3), 3.65 (s, 4 H, NCH2),
3.50 (s, 4 H, NCH2), 3.46 (s, 2 H, ArCH2), 1.26 (m, 12 H,
CO2CH2CH3) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
172.0–171.2 (4 C=O), 154.5 (CIV), 152.9 (CIV), 150.0 (CIV), 149.3
(CIV), 134.2 (CIV), 123.2 (CIV), 118.4 (ArCH), 105.6 (ArCH), 104.9
(ArCH), 61.0–60.0 (4 CO2CH2), 59.1 (ArCH2), 56.7 (OCH3), 56.1
(OCH3), 55.4 (2 NCH2), 55.1 (2 NCH2), 50.4 (ArCH2), 14.4 (4
[2] L. Marion in The Alkaloids (Eds.: R. H. F. Manske, H. L.
Holmes), Academic Press, New York, 1975, p. 209.
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Heterocyclic Chemistry III: A Review of Literature 1982–1995,
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CO CH CH ) ppm. IR (ATR-D): ν = 1735, 1186, 1149, 1027 cm–1.
˜
2
2
3
HRMS (ESI): calcd. for C29H42N3O10 [M + H]+ 592.2870; found
592.2856.
2,2,2ЈЈ,2ЈЈЈ-(5,8-Dimethoxyisoquinoline-1,3-diyl)bis(methylene)bis-
(azanetriyl)tetraacetic Acid (16a): To a solution of tetraester 15a
(1 g, 1 equiv.) in THF/H2O (1:1, 50 mL) was added lithium hydrox-
ide (850 mg, 12 equiv.), and the solution was stirred for 4 h at room
temperature. The solvent was then evaporated, and the crude prod-
uct was purified on Dowex 1X2 100(Cl) ion-exchange resin. The
resin was activated with a solution of sodium hydroxide (1 m,
20 mL) to pH 14 and with water (30 mL) to pH 7. After deposition
of the crude, the impurities were washed with H2O/MeOH (1:1,
100 mL) before elution of the product with pure formic acid. Evap-
oration afforded product 16a (810 mg, 99%) as a yellow powder.
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1
M.p. 140 °C. H NMR (400 MHz, CD3OD, 25 °C): δ = 8.32 (s, 1
H, ArH), 7.50 (d, J = 8 Hz, 1 H, ArH), 7.29 (d, J = 8 Hz, 1 H,
ArH), 5.07 (s, 2 H, ArCH2), 4.43 (s, 2 H, ArCH2), 4.06 (s, 3 H,
OCH3), 4.05 (s, 3 H, OCH3), 3.91 (s, 4 H, NCH2), 3.77 (s, 4 H,
NCH2) ppm. 13C NMR (100 MHz, CD3OD, 25 °C): δ = 174.0 (2
C=O), 173.9 (2 C=O), 158.8 (CIV), 154.3 (CIV), 149.8 (CIV), 142.4
(CIV), 132.9 (CIV), 119.0 (CIV), 117.7 (ArCH), 115.9 (ArCH), 110.7
(ArCH), 60.7 (ArCH2), 57.2–56.0 (ArCH2, 4 CH2N, 2 OCH3) ppm.
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IR (ATR-D): ν = 3000, 2935, 1729, 1368, 1198, 1093, 819 cm–1.
˜
HRMS (ESI): calcd. for C21H24N3O10 [M – H]– 478.1462; found
478.1478.
2,2,2ЈЈ,2ЈЈЈ-(6,7-Dimethoxyisoquinoline-1,3-diyl)bis(methylene)bis-
(azanetriyl)tetraacetic Acid (16b): Same procedure as for compound
2126
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2120–2127

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Received: December 16, 2010
Published Online: March 2, 2011
Eur. J. Org. Chem. 2011, 2120–2127
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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