Synthesis of substituted 2-alkyl-5-hydroxy-1-oxo-1,2-dihydroisoquinolines and their new condensed structures

Article abstract of DOI:10.1016/j.mencom.2010.03.006

Original methods were developed for the synthesis of 1,2-dihydroisoquinoline derivatives by means of the cyclization of N-substituted hexamethoxycarbonyl-3-propenylpyridin-2-ones either upon action of bases or directly by reaction of hepta-(methoxycarbony

Full text of DOI:10.1016/j.mencom.2010.03.006

Mendeleev
Communications
Mendeleev Commun., 2010, 20, 83–85
Synthesis of substituted 2-alkyl-5-hydroxy-1-oxo-
1,2-dihydroisoquinolines and their new condensed structures
Dmitry N. Platonov, Galina P. Okonnishnikova and Yury V. Tomilov*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 495 135 5328; e-mail: tom@ioc.ac.ru
DOI: 10.1016/j.mencom.2010.03.006
Original methods were developed for the synthesis of 1,2-dihydroisoquinoline derivatives by means of the cyclization of
N-substituted hexamethoxycarbonyl-3-propenylpyridin-2-ones either upon action of bases or directly by reaction of hepta-
(methoxycarbonyl)cycloheptatrienyl potassium with primary amines.
Pyridin-2-ones and 1,2-dihydroisoquinolines are widely used
E
N
O
E
E
N
O
E
as central fragments in the synthesis of alkaloids and other
biologically active substances.1 In spite of a variety of methods
for their synthesis, the development of new pathways to such
functionalized compounds is of considerable current interest.
Recently,2 we have found that the reaction of heptamethyl
ester of cycloheptatrieneheptacarboxylic acid 1 with primary
amines is dependent on the reaction conditions and leads to
the formation of N-substituted (heptamethoxycarbonyl)nortrop-
2-enes 2 and/or 3-(1-propenyl)pyridin-3-ones 3, which contain
six ester groups in a molecule (Scheme 1). In methanol, only the
formation of 3-propenylpyridin-3-ones as a mixture of E- and
Z-isomers was observed.
B–
R
E
R
CO2Me
E
– HB
E
E
E
E
E
3a–c
K+
E
N
O
E
E
E
E
O
Y
RNH2
Y = K
R
E
E
E
E
E
E
4a–c
E
E
E
7
H+
E
E
MeI
N
E
E
R
E
N
O
E
E
E
E
E
2
OH
E
OMe
E
E
E
CH2N2
R
R
N
O
+ RNH2
+
E
E
E
E
E
E
E
E
E
E
E
E
E
5a–c
6a–c
1
E
N
R
O
a R = cyclopropyl
b R = Bn
c R = CH2Bn
E = CO2Me
Y = K, PrNH3
E = CO2Me
R = alkyl
3
Scheme 1
Scheme 2
Thus, refluxing pyridinone 3a with isopropylamine in methanol
gives isopropylammonium salt 4a (Y = PrNH3) as the only product
in 91% yield.† The structure of the product was confirmed by 1H
and 13C NMR spectra and X-ray data (Figure 1).‡
Acidification of dihydroisoquinolin-5-olates 4 with mineral
acid solutions affords hydroxy derivatives 5a–c as stable crys-
talline compounds in high yields.§
Since the possibility of cyclization of propenylpyridinones 3
into dihydroisoquinolin-5-olates is determined by their deprotona-
tion degree, we have studied a direct reaction of heptamethoxy-
carbonylcyclohepta-2,4,6-trien-1-yl potassium 7 with cyclo-
propylamine. It was shown previously4 that salt 7 was a stable
compound easily formed from cycloheptatriene 1 upon treat-
ment with potassium tert-butylate. It was found that the
reaction of cyclopropylamine with cycloheptatrienyl potassium
7 in acetonitrile solution at 5 °C during 16 h leads to the
Here, we report that the action of bases upon propenylpyri-
dinones leads to their cyclization into 1-oxodihydroisoquinolin-
5-olates 4a–c, which give 5-hydroxyhydroisoquinolin-1-ones
5a–c in high yields after treatment with an acid (Scheme 2).
The process of cyclization does not depend on the isomeric
composition of starting propenylpyridinones 3a–c, which is
apparently due to both isomers giving the same anion after
deprotonation of the activated methylene group. The formed
anion is able to gain the configuration favouring cyclization to
4a–c at the ester group atattched to C(4) of the pyridine cycle.
A similar cyclization was previously reported in the synthesis
of substituted 10-hydroxyphenanthrenes.3
The rate of cyclization of propenylpyridinones 3 to dihydroxy-
isoquinolin-5-olates 4 depends on the strength of the base used.
With strong bases like KOH, the reaction takes only several
minutes while with primary amines it completes in 10–20 h.
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© 2010 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2010, 20, 83–85
iodide in refluxing acetonitrile during 15 h gives methoxy
derivative 6a in 88% yield (Scheme 2).¶
C(20)
O(10)
These results allowed us to develop a convenient preparative
method to obtain 5-hydroxydihydroisoquinolines 5 starting from
heptamethyl cycloheptatrieneheptacarboxylate 1. This compound
was treated with methanolic KOH; then, a primary amine was
added and the reaction mixture was stirred for 15 h at room
temperature. After acidification to pH 1–2, the reaction mixture
was extracted with chloroform and pure compounds 5a–c were
obtained in high yields.§ The acidity of phenolic protons in com-
pounds 5 is quite high, their treatment with diazomethane in
diethyl ether leads to the formation of methoxy derivatives 6a–c
in a quantitative yield.¶
Further transformations are observed in the reactions of cyclo-
heptatriene 1 with both ethanolamine and ethylenediamine. In
this case, no formation of bicyclic compounds similar to 2 is
observed in either of the solvents used, and the reactions speci-
fically progress towards the formation of the respective 3-vinyl-
pyridin-2-ones. However, the process does not stop at this point.
In case of ethanolamine, product 3d instantly undergoes further
cyclization to lactone 8a, which is easily isolated from the
reaction mixture by crystallization in a yield of 77–80%.2 It
should be noted that lactone 8a is obtained as the E-isomer only
(Scheme 3). Its structure was established by X-ray diffraction
analysis, but crystals were not of good quality and constituted
thin needles having a very low reflecting power.†† Upon treat-
ment of 8a with a base, the second fragment containing an
C(18)
C(22)
O(9)
O(11)
C(19)
C(21)
O(8)
C(17)
C(8)
C(7)
O(12)
C(3S)
C(1S)
C(9)
O(7)
C(4)
C(6)
H(1S1)
C(5)
N(1S)
C(2S)
O(1)
C(3)
C(2)
O(2)
C(11)
N(1)
O(4)
C(15)
O(6)
C(1)
C(10)
C(14)
O(5)
C(12)
C(16)
C(13)
O(3)
Figure 1 Crystal structure of 4a as thermal ellipsoids drawn at 50% prob-
ability level. Selected bond lengths (Å): C(3)–C(6) 1.444(8), C(6)–C(7)
1.426(8), C(6)–O(2) 1.293(7), C(1S)–C(2S) 1.524(9), C(1S)–C(3S) 1.507(9),
C(1S)–N(1S) 1.472(8), O(2)···HN(1S) 1.81.
formation of potassium dihydroisoquinolin-5-olate 4a (Y = K)
in a yield of ³ 85%. Acidification of the resulting potassium
phenolate to pH 1–2 gives phenol 5a. Its reaction with methyl
†
Isopropylammonium 2-cyclopropyl-3,4,6,7,8-penta(methoxycarbonyl)-
1-oxo-1,2-dihydroisoquinolin-5-oate 4a (Y = PrNH3). The mixture of
dihydropyridinone 3a (315 mg, 0.6 mmol) and 2-aminopropane (83 mg,
1.4 mmol) in methanol (10 ml) was refluxed for 14 h. Evaporation in vacuo
and crystallisation of the residue from acetonitrile gave salt 4a as light
yellow crystals, yield 91%, mp 181–182 °C (decomp.). 1H NMR (CDCl3,
300 MHz) d: 0.79, 1.07 (both m, 2×2H, CH2CH2), 1.09 (d, 6H, 2Me,
J 6.5 Hz), 3.18 (tt, 1H, CH in cyclopropyl, Jcis 7.1 Hz, Jtrans 4.0 Hz), 3.24
(sp, 1H, NCH, J 6.5 Hz), 3.78, 3.80, 3.83, 3.91, 3.94 (all s, 5×3H, 5OMe),
6.93 (br. s, 3H, CN+H3). 13C NMR (CDCl3, 75.5 MHz) d: 8.7 (CH2CH2),
21.8 (2Me), 31.5 (CH in cyclopropyl), 43.9 (CH in Pr), 52.6, 52.8, 52.9,
52.9, 53.2 (5OMe), 113.2 (4-C), 118.2, 118.4 (4a-C, 6-C), 126.0, 128.4,
132.4, 134.3 (3-C, 7-C, 8-C, 8a-C), 161.1, 162.5, 163.5, 167.7, 169.1,
169.4, 169.6 (1-C, 5-C, 5COO). Found (%): C, 54.63; H, 5.23; N, 5.13.
Calc. for C25H30N2O12 (%): C, 54.54; H, 5.49; N, 5.09.
Potassium 2-cyclopropyl-3,4,6,7,8-penta(methoxycarbonyl)-1-oxo-1,2-
dihydroisoquinolin-5-oate 4a (Y = K). The mixture of heptamethoxy-
carbonylcyclohepta-2,4,6-trien-1-yl potassium4 (485 mg, 0.9 mmol) and
cyclopropylamine (80 mg, 1.4 mmol) in acetonitrile (2.5 ml) was kept at
5 °C for 16 h. Evaporation in vacuo and crystallisation of the residue
from benzene gave salt 4a (Y = K) as yellow crystals, yield 85%,
mp 241–242 °C (decomp.). 1H NMR (CDCl3, 300 MHz) d: 0.89, 1.18
(both m, 2×2H, CH2CH2), 3.34 (tt, 1H, CH in cyclopropyl, Jcis 7.1 Hz,
Jtrans 4.1 Hz), 3.93, 3.96, 3.97, 3.99, 4.00 (all s, 5×3H, 5OMe). 13C NMR
(CDCl3, 75.5 MHz) d: 8.7 (CH2CH2), 31.5 (CH in cyclopropyl), 52.2,
52.9, 53.0, 53.1, 53.3 (5OMe), 114.5 (4-C), 125.8, 125.9 (4a-C, 6-C),
128.8, 132.6, 133.4, 133.5 (3-C, 7-C, 8-C, 8a-C), 161.9, 162.9, 163.0,
169.0, 169.9, 170.5, 171.1 (1-C, 5-C, 5COO). Found (%): C, 50.11;
H, 3.63; N, 2.52. Calc. for C22H20KNO12 (%): C, 49.90; H, 3.81; N, 2.65.
§
General method for the synthesis of compounds 5a–c. Heptamethoxy-
carbonylcyclohepta-1,3,5-triene 1 (200 mg, 0.4 mmol) was added to a
solution of KOH (26 mg, 0.4 mmol) in methanol (5 ml) and the mixture
was stirred for 30 min. Then an amine (0.4 mmol) was added to a
reaction mixture and the mixture was stirred for 6–7 h at 25 °C (TLC).
The solvent was removed in vacuo, 5% aqueous H2SO4 solution was
added to pH ~1.5, and the mixture was extracted with chloroform.
The organic layer was dried with Na2SO4 and the solvent was removed
in vacuo. The products were obtained as colourless crystals.
Pentamethyl 2-cyclopropyl-5-hydroxy-1-oxo-1,2-dihydroisoquinoline-
3,4,6,7,8-pentacarboxylate 5a. Yield 88%, mp 195–196 °C (MeCN).
1H NMR (CDCl3, 300 MHz) d: 0.84, 1.11 (both m, 2×2H, CH2CH2), 3.21
(tt, 1H, CH in cyclopropyl, Jcis 7.2 Hz, Jtrans 4.1 Hz), 3.62, 3.83, 3.90, 3.94,
3.98 (all s, 5×3H, 5OMe), 12.1 (s, 1H, OH). 13C NMR (CDCl3, 75.5 MHz)
d: 8.8 (CH2CH2), 31.7 (CH in cyclopropyl), 53.1, 53.2 (2C), 53.5, 53.9
(5OMe), 110.6, 110.7 (4-C, 6-C), 124.6, 125.0, 127.1 (4a-C, 8-C, 8a-C),
133.1, 137.3 (3-C, 7-C), 158.4, 158.5 (1-C, 5-C), 159.9, 161.9, 166.5, 167.6,
169.1 (5COO). MS, m/z (%): 491 (3) [M]+, 432 (5) [M – CO2Me]+, 400
(11), 368 (10), 336 (11), 59 (40), 41 (100). Found (%): C, 54.00; H, 4.38;
N, 2.70. Calc. for C22H21NO12 (%): C, 53.77; H, 4.28; N, 2.85.
Pentamethyl 2-benzyl-5-hydroxy-1-oxo-1,2-dihydroisoquinoline-3,4,6,7,8-
pentacarboxylate 5b. Yield 93%, mp 212–213 °C (MeCN). 1H NMR
(CDCl3, 300 MHz) d: 3.88, 3.89, 3.95, 3.96, 3.98 (all s, 5×3H, 5OMe),
5.47 (s, 2H, CH2), 7.16 (dd, 2H, 2Ho, 3J 7.7 Hz, 4J 2.2 Hz), 7.28 (m, 3H,
2Hm, Hp), 12.1 (s, 1H, OH). 13C NMR (CDCl3, 75.5 MHz) d: 48.4 (CH2),
53.1, 53.2, 53.3, 53.5, 54.0 (5OMe), 110.8 (4-C), 125.1, 125.2, 126.9
(4a-C, 6-C, 8-C), 133.1, 135.5, 135.6, 135.8 (Ci, 3-C, 7-C, 8a-C), 158.6
(2C), 159.1, 162.1, 166.6, 167.8, 169.1 (1-C, 5-C, 5COO). MS, m/z (%):
509 (5) [M – MeOH]+, 388 (11), 356 (15), 121 (21), 91 (100). Found (%):
C, 57.45; H, 4.22; N, 2.50. Calc. for C26H23NO12 (%): C, 57.67; H, 4.25;
N, 2.59.
Pentamethyl 2-(2-phenylethyl)-5-hydroxy-1-oxo-1,2-dihydroisoquinoline-
3,4,6,7,8-pentacarboxylate 5c. Yield 95%, mp 175–176 °C (C6H6). 1H NMR
(CDCl3, 300 MHz) d: 3.04 (m, 2H, CH2), 3.88, 3.90, 3.92, 3.96, 3.97
(all s, 5×3H, 5OMe), 4.18 (m, 2H, NCH2), 7.27 (m, 5H, Ph), 12.1 (s,
1H, OH). 13C NMR (CDCl3, 75.5 MHz) d: 34.8 (CH2), 49.2 (NCH2),
53.1 (2C), 53.2, 53.8, 53.9 (5OMe), 110.0, 110.6 (4-C, 6-C), 125.0,
125.1, 126.8 (4a-C, 8-C, 8a-C), 132.8, 136.5, 137.7 (Ci, 3-C, 7-C), 158.5,
158.6 (1-C, 5-C), 162.3, 166.6, 166.7, 167.8, 169.1 (5COO). MS, m/z (%):
555 (5) [M]+, 492 (10), 451 (20), 419 (50), 387 (50), 356 (20), 329 (31),
271 (26), 105 (100). Found (%): C, 57.99; H, 4.47; N, 2.49. Calc. for
C27H25NO12 (%): C, 58.38; H, 4.54; N, 2.52.
‡
Crystallographic data for 4a (Y = PrNH3). Crystals of C25H30N2O12
(M = 550.51) are orthorhombic, space group Pca21, at 120(2) K: a =
= 23.829(7), b = 13.374(3) and c = 8.533(2) Å, V = 2719.3(12) Å3, Z = 4,
F(000) = 1160, dcalc = 1.345 g cm–3, m = 0.108 mm–1. Intensities of 25922
reflections were measured on an automated SMART 1000 CCD dif-
fractometer (MoKα radiation, graphite monochromator, j and w-scanning
techniques, qmax = 28°). The structure was solved by direct methods and
refined by a full-matrix least-squares method against F2 in the anisotropic–
isotropic approximation. The positions of the hydrogen atoms were cal-
culated geometrically. The final R factors were as follows: R1 = 0.0745
for 3481 independent reflections with I > 2s(I) and wR2 = 0.1398 for all
1755 independent reflections, GOF = 1.101. All calculations were carried
out using the SHELXTL PLUS software (Version 5.0).
CCDC 749953 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2010.
– 84 –

Mendeleev Commun., 2010, 20, 83–85
active methylene group undergoes cyclization. Acidification of
OMe
the phenolate affords derivative 9a.‡‡ The same compound is
easily obtained as a phenolate in one pot if KOH is initially
added to triene 1.
O
E
HX
N
O
E
1 + HXCH2CH2NH2
In case of ethylenediamine, which is a quite strong base,
lactam 8b could not be detected as the propenylpyridine frag-
E
E
E
¶
2-Cyclopropyl-3,4,6,7,8-penta(methoxycarbonyl)-1-oxo-5-methoxy-1,2-
X = NH
dihydroisoquinoline 6a. A solution of compound 4a (Y = K) (160 mg,
0.3 mmol) and methyl iodide (71 mg, 0.5 mmol) in acetonitrile (4 ml)
was refluxed for 15 h. After cooling, filtration, evaporation of the filtrate
in vacuo and crystallisation from CH2Cl2–CCl4 (10:1) compound 6a
was obtained as light yellow crystals, yield 88%, mp 154–155 °C. 1H NMR
(CDCl3, 300 MHz) d: 0.85, 1.10 (both m, 2×2H, CH2CH2), 3.18 (tt, 1H,
CH in cyclopropyl, Jcis 7.0 Hz, Jtrans 4.1 Hz), 3.76 (s, 3H, OMe), 3.86,
3.88, 3.94, 3.96, 4.01 (all s, 5×3H, 5OMe). 13C NMR (CDCl3, 75.5 MHz)
d: 8.7 (CH2CH2), 31.6 (CH in cyclopropyl), 53.2, 53.3, 53.4, 53.5, 53.6
(5OMe), 64.9 (OMe), 109.9 (4-C), 125.2, 129.2 (4a-C, 8-C), 131.0,
131.2, 132.0 (7-C, 6-C, 8a-C), 138.4 (3-C), 154.0 (5-C), 160.1 (1-C),
161.9, 164.6, 165.7, 166.5, 167.7 (5COO). MS, m/z (%): 505 (3) [M]+,
490 (12), 474 (10), 446 (22), 414 (20), 199 (50), 185 (60), 171 (55),
158 (47), 143 (57), 128 (65), 114 (100). Found (%): C, 54.27; H, 4.49;
N, 2.85. Calc. for C23H23NO12 (%): C, 54.66; H, 4.59; N, 2.77.
X = O
O
O
O
E
X
E
OH
E
B–
N
O
CO2Me
E
N
O
E
E
E
E
8a
9a,b
E = CO2Me
a X = O
b X = NH
Scheme 3
Pentamethyl 2-(2-phenylethyl)-5-methoxy-1-oxo-1,2-dihydroisoquinoline-
3,4,6,7,8-pentacarboxylate 6c. A solution of diazomethane in Et2O (1 ml,
~0.5 mmol) was added in one portion to a solution of 5c (112 mg,
0.2 mmol) in CH2Cl2 (4 ml) and the mixture was stirred at room tem-
perature for 1 h. Yield 99%, mp 186–187 °C (MeCN). 1H NMR (CDCl3,
300 MHz) d: 3.05 (m, 2H, CH2), 3.76 (s, 3H, OMe), 3.85, 3.90, 3.93,
3.95, 4.03 (all s, 5×3H, 5CO2Me), 4.16 (m, 2H, NCH2), 7.29 (m, 5H,
Ph). 13C NMR (CDCl3, 75.5 MHz) d: 34.8 (CH2), 49.1 (NCH2), 53.1,
53.2, 53.3, 53.4, 53.9 (5OMe), 64.9 (OMe), 109.1 (4-C), 124.9 (8-C),
131.3, 131.4, 132.1 (4a-C, 6-C, 8a-C), 137.5, 137.6, 137.7 (Ci, 3-C, 7-C),
154.0, 158.8 (1-C, 5-C), 162.2, 164.6, 165.7, 166.7, 167.9 (5COO). MS,
m/z (%): 569 (10) [M]+, 538 (15), 464 (29), 432 (50), 401 (40), 387 (21),
373 (25), 105 (100). Found (%): C, 58.89; H, 4.69; N, 2.40. Calc. for
C28H27NO12 (%): C, 59.05; H, 4.75; N, 2.46.
ment of this compound immediately cyclised into the phenolate,
which upon acidification gives condensed phenol 9b in 90%
yield (Scheme 3).
Thus, using the reactions of cycloheptatrieneheptacarboxylic
acid heptamethyl ester with primary amines in various basic
environments we have developed a new approach to the syn-
thesis of polyfunctionalized condensed heterocyclic compounds
containing a dihydroisoquinolin-1-one fragment.
This work was supported by the Presidium of the Russian
Academy of Sciences (Program for Basic Research ‘Elaboration
of Methods for the Synthesis of Chemical Substances and Creation
of New Materials’) and the Council on Grants of the President
of the Russian Federation (grant no. NSh-3237.2008.3).
We are grateful to Dr. K. Yu. Suponitsky (A. N. Nesmeyanov
Institute of Organoelement Compounds, Russian Academy of
Sciences) for the execution of X-ray diffraction analyses.
†† CCDC 756669 contains the supplementary crystallographic data for
8a, which were obtained earlier.2 These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
‡‡ Tetramethyl 10-hydroxy-1,6-dioxo-1,3,4,6-tetrahydro[1,4]oxazino[4,3-b]-
isoquinoline-7,8,9,11-tetracarboxylate 9a. This compound was obtained
according to the general method for the synthesis of compounds 5a–c.
Yield 84%, mp 226–228 °C (MeOH). 1H NMR (CDCl3, 300 MHz) d:
3.90, 3.95, 3.98, 4.00 (all s, 4×3H, 4OMe), 4.34 (m, 2H, NCH2), 4.63 (t,
2H, OCH2, J 4.8 Hz), 12.3 (s, 1H, OH). 13C NMR (CDCl3, 75.5 MHz) d:
40.0 (NCH2), 53.1, 53.2, 53.3, 54.0 (4OMe), 65.2 (OCH2), 111.2 (11-C),
116.9 (9-C), 124.5, 124.8, 126.3, 134.2 (6a-C, 7-C, 8-C, 10a-C), 157.0,
157.5, 159.3, 159.4 (1-C, 6-C, 10-C, 11a-C), 166.0, 166.1, 167.3, 168.7
(4COO). MS, m/z (%): 431 (4) [M – MeOH]+, 400 (5), 359 (6), 283
(15), 59 (100). Found (%): C, 51.79; H, 3.51; N, 3.09. Calc. for
C20H17NO12 (%): C, 51.84; H, 3.70; N, 3.02.
Tetramethyl 10-hydroxy-1,6-dioxo-1,3,4,6-tetrahydro-2H-pyrazino-
[1,2-b]isoquinoline-7,8,9,11-tetracarboxylate 9b. Yield 87%, mp > 240 °C
(decomp.). 1H NMR ([2H6]DMSO, 300 MHz) d: 3.47, 4.12 (both m,
2×2H, CH2CH2), 3.73, 3.76, 3.77, 3.80 (all s, 4×3H, 4OMe), 8.80 (br. s,
1H, NH), 11.5 (br. s, 1H, OH). 13C NMR (CDCl3, 75.5 MHz) d: 36.6
(3-C), 40.3 (4-C), 51.5, 51.9, 52.5, 52.6 (4OMe), 111.7 (11-C), 120.7
(9-C), 124.2, 126.3, 129.9, 131.0 (6a-C, 7-C, 8-C, 10a-C), 152.2, 156.8,
157.5, 157.6 (1-C, 6-C, 10-C, 11a-C), 165.0, 165.1, 166.1, 166.8 (4COO).
Found (%): C, 51.71; H, 3.98; N, 5.97. Calc. for C20H18N2O11 (%):
C, 51.95; H, 3.92; N, 6.06.
References
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Received: 13th October 2009; Com. 09/3401
– 85 –