An efficient method for the preparation of antitumoral α-keto-imines benzyldihydroisoquinolines by selective benzylic oxidation with C/Pd in acetonitrile

Article abstract of DOI:10.1016/S0040-4039(01)02257-2

A series of potent antitumor α-keto-imine BDHIQ derivatives were synthesized and assayed in vitro against L1210 leukemia cell line. A new and easy method for the direct formation of α-keto-imine from imine BDHIQ's was performed with 10% C/Pd in acetonitrile.

Full text of DOI:10.1016/S0040-4039(01)02257-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 757–759
An efficient method for the preparation of antitumoral
a-keto-imines benzyldihydroisoquinolines by selective benzylic
oxidation with C/Pd in acetonitrile
Inmaculada Andreu,a Nuria Cabedo,a Ghanem Atassi,b Alain Pierre,b Daniel H. Caignard,b
Pierre Renard,b Diego Cortesa,* and Almudena Bermejoa
aDepartamento de Farmacolog´ıa, Farmacognosia y Farmacodinamia, Facultad de Farmacia, Universidad de Valencia,
46100 Burjassot, Valencia, Spain
bLaboratoire Servier, 92415 Courbevoie, France
Received 22 October 2001; accepted 14 November 2001
Abstract—A series of potent antitumor a-keto-imine BDHIQ derivatives were synthesized and assayed in vitro against L1210
leukemia cell line. A new and easy method for the direct formation of a-keto-imine from imine BDHIQ’s was performed with 10%
C/Pd in acetonitrile. © 2002 Elsevier Science Ltd. All rights reserved.
In order to prepare a-keto-imine 1-benzyldihydroiso-
quinolines (BDHIQ), several oxidation methods of
imines have been described.1–7 These methods include
the spontaneous oxidation of benzylic carbons,1,2 the
photooxidation by exposition to singlet oxygen3,4 and
the oxidizing reagent treatments such as lead tetra-
cetate, manganese dioxide, and diacetoxyiodobenzene.5–7
The keto-imines prepared by these procedures were
obtained in a variable yield.1–7
dihydropyridine cycle of the BDHIQ was not observed
by this procedure; so, oxidation at the exo benzylic
carbon is faster than at the endo position of the hetero-
cycle. The a-keto-imines obtained were stored as their
salt forms.
This method, for the preparation of a-keto-imines (II),
was applied to a series of BDHIQ’s with several substi-
tution patterns, both in the dihydroisoquinoline and the
benzylic rings. The a-keto-imines obtained from an
unsubstituted benzylic ring were furnished in typical
90% yields (compounds II1 to II15). However, when
the BDHIQ’s mono or disubstituted on the benzene
ring of the benzylic moiety were treated by the same
reagents for 3 h, the corresponding a-keto-imines (com-
pounds II16 to II26) were obtained in a lesser yield.
We have prepared a series of a-keto-imine BDHIQ’s, as
a new class of antitumor compounds with in vitro
potent effect against L1210 leukemia cells. This activity
was also reflected by their ability to perturbate the cell
cycle inducing an accumulation of cells in the G1
phase.8 This phase is an important period where vari-
ous complex signals interact to decide a cell’s fate: e.g.
proliferation, quiescence, differentiation or apoptosis.
The a-keto-imine BDHIQ’s obtained (compounds II),
1
were easily identified by H NMR due to both charac-
The preparation of the title compounds was accom-
plished at room temperature during 1 h in dry acetoni-
trile over 10% C/Pd.9 Under these conditions the
imines-BDHIQ’s (I)10–14 were directly transformed into
a-keto-imines (II) in a good yield (see Scheme 1).15 It is
interesting to note, that the total oxidation of the
teristic systems, a dd deshielded signal at about l 8.0
(H-2% and H-6%), corresponding to two of the aromatic
benzylic protons affected by the anisotropic effect of
the carbonyl group, and an A2B2 system, at about l
3.90 and l 2.75, corresponding to the methylenes
placed on the dihydroisoquinoline moiety (CH2-3 and
CH2-4).
Indeed, the absence of the benzylic methylene in com-
pounds II can be determined by NMR spectra16 and
confirmed by the presence of the characteristic ketone
carbon signal at about 194 ppm.
Keywords: a-keto-imines; benzyldihydroisoquinolines; C/Pd, acetoni-
trile; selective oxidation; antitumoral.
* Corresponding author. Tel.: (34) 96 386 49 75; fax: (34) 96 386 49
43; e-mail: dcortes@uv.es
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02257-2

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I. Andreu et al. / Tetrahedron Letters 43 (2002) 757–759
Scheme 1.
tion was carried out for 30 min only. After sephadex
purification, compound III was obtained in 10% yield,
but 50% of the starting material III6 was also obtained
(Scheme 2).
This procedure has also been applied to the preparation
of a new type of trans-styryl isoquinolines (III) (see
Scheme 2). The acetoamide (III6) was prepared from
isovanillin (III1) by a classic methodology,11–14 includ-
ing the Schotten–Baumann condensation between a
phenylethylamine (III5) and the corresponding trans-
styryl acetyl chloride (III4). Under these reaction condi-
tions, III6 was obtained in an overall yield of 50%. The
synthesis of the subsequent a-keto-imine trans-styryl
dihydroisoquinoline (III) was performed in an ‘one-pot’
sequence in two steps. The acetamide (III6) was first
refluxed in CH2Cl2 in the presence of POCl3, in a
cyclodehydratation Bischler–Napieralski experiment.
The reaction mixture was directly treated in acetonitrile
by 10% C/Pd, and 5% NH4OH. Because this type of
conjugated styryl keto-imine is very unstable this reac-
All the a-keto-imines BDHIQ derivatives were tested in
vitro against L1210 leukemia cells. II1, II21 and II22
(IC50 4.1, 2.5 and 1.4 mM, respectively) were the most
potent to inhibit the proliferation of L1210 cells. Fur-
thermore, these a-keto-imines BDHIQ induced an accu-
mulation of L1210 cells in the G1 phase of the cell
cycle.8
In conclusion, we have prepared a series of a-keto-
imines BDHIQ’s by a simple and efficient method
which can be applied for the synthesis of new antitu-
moral agents.

I. Andreu et al. / Tetrahedron Letters 43 (2002) 757–759
759
de´rive´s d’Isoquinole´ines, leur procede´ de pre´paration et
les compositions pharmaceutiques qui les contiennent.
Patent no. P2000/000185, 28.01.2001.
9. This controlled oxidation was previously performed on
the preparation of enamines with an aporphine skeleton:
Cava, M. P.; Edie, D. L.; Saa´, J. M. J. Org. Chem. 1975,
40, 3601–3602.
10. Prepared by classic Bischler–Napieralski cyclodehydrata-
tion experiments.11–14
11. Cabedo, N.; Protais, P.; Cassels, B. K.; Cortes, D. J. Nat.
Prod. 1998, 61, 709–712.
12. Andreu, I.; Cortes, D.; Protais, P.; Cassels, B. K.;
Chagraoui, A.; Cabedo, N. Bioorg. Med. Chem. 2000, 8,
889–895.
13. Andreu, I.; Cabedo, N.; Tormo, J. R.; Bermejo, A.;
Mello, R.; Cortes, D. Bioorg. Med. Chem. Lett. 2000, 10,
1491–1494.
14. Cabedo, N; Andreu, I.; Ram´ırez de Arellano, M. C.;
Chagraoui, A.; Serrano, A.; Bermejo, A.; Protais, P.;
Cortes, D. J. Med. Chem. 2001, 44, 1794–1801.
15. General procedure for preparation of a-keto-imines
BDHIQs: synthesis of 6-benzyloxy-7-methoxy-a-keto-3,4-
benzyldihydroisoquinoline (II1). A solution of N-(3-ben-
zyloxy-4-methoxyphenylethyl) phenylacetamide (500 mg,
1.33 mmol) in dry CH2Cl2 (10 mL) was treated with
POCl3 (0.5 mL, 5.4 mmol) and refluxed for 3 h. The
reaction mixture was diluted with H2O, made basic and
extracted with CH2Cl2. The organic solution was washed
with H2O, dried and concentrated to give a brown oil.
This residue was purified through 60 H silicagel column
(CH2Cl2–MeOH 96:4) to afford the corresponding imine,
I1 (415 mg, 87%). I1 (150 mg, 0.42 mmol) was treated
with CH3CN (70 mL) and 10% C/Pd (150 mg) and
stirring for 1 h at room temperature. The reaction mix-
ture was filtered over Celite and concentrated. The
residue obtained was purified through 60 H silicagel
column (hexane–EtOAc 60:40) to yield 6-benzyloxy-7-
methoxy-a-keto-3,4-benzyldihydroisoquinoline, II1 (141
mg, 90%), and its salt was prepared from 5% HCl in
MeOH. C24H21NO3; 1H NMR* (400 MHz, CDCl3) l
8.03 (dd, J=7.0, 1.7 Hz, 2H, H-2%,6%), l 7.59 (tt, J=7.0,
1.7 Hz, 1H, H-4%), l 7.45 (t, J=7.0 Hz, 2H, H-3%,5%), l
7.50–7.30 (m, 5H, OCH2Ph-6), l 6.97 (s, 1H, H-5), l 6.77
(s, 1H, H-8), l 5.21 (s, 2H, OCH2Ph-6), l 3.90 (t, J=7.8
Hz, 2H, CH2-3), l 3.78 (s, 3H, OCH3-7), l 2.75 (t, J=7.8
Hz, 2H, CH2-4); 13C NMR* (100 MHz, CDCl3) l 193.9
(C-a), l 164.3 (C-1), l 150.9 (C-6), l 148.2 (C-7), l 136.4
and 135.5 (C-1% and C-1%%), l 133.8 (CH-4%), l 130.9
(C-4a), l 130.4 (CH-2%,6%), l 130.3 (CH-3%,5%), l 128.6–
127.2 (OCH2Ph-6), l 119.6 (C-8a), l 112.7 (CH-8), l
110.2 (CH-5), l 70.8 (OCH2Ph-6), l 56.2 (OCH3-7), l
42.2 (CH2-3), l 25.3 (CH2-4); EIMS m/z (%) 371 [M]+
(36), 280 (61), 266 (4), 105 (25), 91 (100), 77 (27). *The
assignments were made by COSY 45, DEPT and HMQC.
16. The imines BDHIQ (compounds I) showed characteristic
Scheme 2. Reagents and conditions: (i) PhCH2Cl, K2CO3,
EtOH, refluxed 5 h; (ii) CH3NO2, NH4OAc, AcOH, refluxed
4 h; (iii) THF, LiAlH4, Et2O, N2 atm, refluxed 2 h; (iv)
CH2Cl2, 5% aq. NaOH, 0°C, rt, 2 h; (v) POCl3, dry CH2Cl2,
refluxed 1.5 h; (vi) CH3CN, 10% C/Pd, 5% aq. NH4OH, 30
min.
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