Synthesis of tetracyclic dioxygenated isoquinolines and their cytotoxic activity

Article abstract of DOI:10.1016/j.tet.2008.09.097

An efficient synthesis of new dioxygenated isoquinolines is reported. The novelty of this approach derives from its use of tricyclic-nitril (3) as a building block in a synthetic sequence of seven steps for the preparation of the tetracyclic isoquinoline (14) and its derivatives. The isoquinoline 16 was 10-fold more active against leukemia L₁₂₁₀ than the corresponding tetrahydroisoquinoline 14.

Full text of DOI:10.1016/j.tet.2008.09.097

Tetrahedron 64 (2008) 11020–11027
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of tetracyclic dioxygenated isoquinolines
and their cytotoxic activity
,
Manel Romero a, Daniel-Henry Caignard b, Pierre Renard b, M. Dolors Pujol a
*
a
`
Laboratori de Qu´ımica Farmace`utica (Unitat Associada al CSIC), Facultat de Farmacia, Universitat de Barcelona, Av. Diagonal 643, 08028 Barcelona, Spain
b Laboratoires Servier, Courbevoie Cedex, Paris, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of new dioxygenated isoquinolines is reported. The novelty of this approach de-
rives from its use of tricyclic-nitril (3) as a building block in a synthetic sequence of seven steps for the
preparation of the tetracyclic isoquinoline (14) and its derivatives. The isoquinoline 16 was 10-fold more
active against leukemia L1210 than the corresponding tetrahydroisoquinoline 14.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 8 August 2008
Received in revised form 26 September
2008
Accepted 29 September 2008
Available online 8 October 2008
Keywords:
Polycyclic compounds
Phenethylamine derivatives
Dioxygenated isoquinoline
Antitumor compounds
1. Introduction
2. Results and discussion
Due to their biological applicability and their value as
synthetic intermediates, the isoquinoline family has received in-
creased interest.1,2 Many different routes have been published for
the preparation of biologically active isoquinolines and the
strategies that utilize reactions, which rapidly assemble the
skeletal framework of tetracyclic isoquinolines have been
preferred.3
Isoquinoline derivatives are a pharmacologically interesting
class of heterocycles. This heterocyclic system forms part of potent
antitumoral agents associated with topoisomerase II4 and top-
oisomerase I inhibitors.5
Only a few methods for the synthesis of polycyclic isoquino-
lines are reported.6 Our approach is simple and constitutes
a practical route to this class of dioxygenated isoquinolines or their
saturated analogues. This paper is the continuation of a previous
study.7
We report our efforts toward the synthesis of tetracyclic iso-
quinolines containing the 1,4-benzodioxin subunit and we discuss
their future application to the synthesis of substituted tetrahy-
droisoquinolines with potential antitumor activity.
Starting compounds 5, 7, and 8 in this synthetic sequence
were prepared by the Diels–Alder reaction of the diene 18 with
acrylonitrile. The adduct 2 was transformed into the key in-
termediate 3 by treatment with t-BuOK in THF. The catalytic
hydrogenation of 3 in the presence of PtO2 at room temperature
yielded the amine 8 in quantitative yield. Treatment of 3 with
DIBAL-H in THF furnished the aldehyde 4, which was reduced
with NaBH4 to the corresponding benzylalcohol 5. Moreover,
the reaction of 4 with nitromethane in basic media led to the
isolation of the nitroalcohol 6 in 71% yield, which gave the
aminoalcohol 7 after reduction of the nitro function by catalytic
hydrogenation (Scheme 1).
Compounds 5 and 6 are good candidates for the preparation of
the b-phenethylamine 11, whereas in the assays carried out the
aminoalcohol 7 did not allow the preparation of the desired iso-
quinoline. Treatment of 5 with thionyl chloride in toluene followed
by nucleophilic substitution of the chloromethyl derivative 9 by
potassium cyanide gave the expected amine 11. Also the nitro-
alcohol 6 can be easily transformed to 11 by dehydration followed
by reduction (Scheme 2).
A few years ago, we reported the synthesis of tricyclic iso-
quinolines containing the 1,4-benzodioxin by different synthetic
strategies.7 In this study, we initially used the classic Bischler–
Napieralski reaction to prepare the isoquinoline 16 from the
corresponding amide 15. However, the yields were low, so we
* Corresponding author. Tel.: þ34 93 402 4534; fax: þ34 93 403 5941.
E-mail address: mdpujol@ub.edu (M.D. Pujol).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.097

M. Romero et al. / Tetrahedron 64 (2008) 11020–11027
11021
CH3
CH3
O
CH3
CH3
CH3
O
O
O
CN
O
O
CN
O
O
CHO
O
O
(5 eq)
CN
t-BuOK (1eq)
1) DIBAL (1eq)
80°, 60h
THF, rt, 30 min
93%
5 min
4
2) HCl, rt
CH3
CH3
CH3
88%
1
2
3
NaBH4(2.2eq)
1) CH3NO2(1.1 eq)/BuLi (1.2 eq)
(-78 °C, 30 min); 2) H2O
71%
H
2 /PtO2
MeOH, rt,
MeOH
rt, 12h
95%
30 min
99%
CH3
CH3
OH
CH3
CH3
O
O
CH2OH
O
O
O
CH2NH2
NO2
O
5
CH3
6
CH3
8
1) H2/Pd-C, MeOH, rt,
12 h
96%
CH3 OH
O
O
NH2
7
CH3
Scheme 1.
CH3
CH3
CH3
SOCl2 (12.7 eq)
toluene, 120°
15h
CH3
O
O
CH2CN
H2/PtO2, AcOEt
O
O
CH2Cl
KCN(2 eq)
O
5
NH2
87%
DMF/HMPT
rt, 12h
rt, 12h
O
10
95%
9
11
CH3
CH3
81%
1) P2O5 (2 eq)/CH2Cl2
rt, 2h
2) H2/Pd-C, AcOEt
rt, 3 days
61%
6
Scheme 2.
attempted to change the cyclization step. Thus, the phenethylamine
11 was treated with the 3,4,5-trimethoxybenzaldehyde in classic
conditions for imine formation. A mixture of trifluoroacetic acid
and trifluoroacetic anhydride was then added. The resulting
trifluoroacetamide 13 was hydrolyzed with 2 N NaOH at room
temperature and the isoquinoline 14 was obtained in good yield
after purification (Scheme 3).
The tetrahydroisoquinoline 14 was converted to the isoquino-
line 16 by heating a decalin solution of 14 in the presence of 10%
Pd/C. On the other hand, the treatment of 14 with Ag2O in
dichloromethane gave dihydroisoquinoline 17 in 41% yield. Like-
wise, the treatment of the dihydroisoquinoline 17 with Pd/C in
refluxing decalin gave the same isoquinoline 16 in acceptable yield
(Scheme 4).
The tetrahydroisoquinoline 14 was treated with halogenated
compounds to give the N-alkylated derivatives 18 and 19. The ester
19 was hydrolyzed with 2 N NaOH to afford the carboxylic acid 20
in good yield (Scheme 5).
Similarly, carbamates 21–23 were prepared from the benzylic
amine 8, which was reacted with the appropriate chloroformate in
dichloromethane (Scheme 6).
Compounds 14, 16, and 18–23 were synthesized to explore the
structure–activity relationship. To examine the effect of the iso-
quinoline nucleus on cytotoxic activity, various substituents were
CH3
CH3
CH3
3,4,5-trimethoxybenzaldehyde
O
O
O
O
O
(1.1 eq)
CF3COOH (16 eq)
N
NR
NH2
APTS, toluene, reflux,12h
95%
(CF3CO)2O (8.6 eq)
O
rt, 12h
71%
12
11
CH3 Ar
CH3 Ar
13 R = COCF3
14 R = H
CH3
NaOH, rt, 12h
86%
Ar = 3,4,5-trimethoxyphenyl
CH3 OH
CH3
CH3 OH
O
O
O
POCl3
O
ArCOCl (1eq)
O
Et3N / CH2Cl2
rt, 1h
HN
N
NH2
O
15
O
16
CH3
CH3 Ar
Ar = 3,4,5-trimethoxyphenyl
Ar
96%
CH3
7
Scheme 3.

11022
M. Romero et al. / Tetrahedron 64 (2008) 11020–11027
Ag2O (4 eq), CH2Cl2, reflux, 4 days
41%
CH3
CH3
O
CH3
O
O
O
O
Pd/C
N
decalin
Pd/C, decalin
NH
N
220°, 1day
69%
O
220°, 1day
CH3 Ar
55%
CH3 Ar
14
CH3 Ar
16
17
Ar = 3,4,5-trimethoxyphenyl
Scheme 4.
CH3
CH3
O
O
O
O
R-X (1.3 eq)
18 R = -(CH2)2N(CH2CH3)2 (65%)
19 R = -(CH2)5COOMe
20 R = -(CH2)5COOH
(67%) NaOH2N,
MeOH, rt, 6h
NR
NH
K2CO3/DMF
rt, 60h
(94%)
CH3 Ar
CH3 Ar
14
Scheme 5.
CH3
CH3
O
O
O
O
O
NH2
OR 21 R = benzyl (96%)
22 R = allyl (83%)
23 R = propargyl (89%)
N
H
ROCOCl (1.1eq)
Et3N /CH2Cl2
rt, 30 min
8
CH3
CH3
Scheme 6.
introduced at the N-atom. The marked difference in activity among
the isoquinoline derivatives and the carbamates indicated the im-
portance of the tetracyclic system. The presence of substituents on
the N-atom reduced the activity, while the absence of substituents
and the presence of the isoquinoline subunit are cooperative de-
terminants of potent cytotoxicity.
The cytotoxicity experiment of the synthesized compounds was
performed in vitro against tumor cell line L1210. The IC50 cytotox-
icity values obtained are summarized in Table 1. Tetracyclic
compounds 14, 16, 18 and 19 displayed micromolar cytotoxicity
concentrations.
3. Experimental section
3.1. General
Melting points were obtained on an MFB-595010 M Gallenkamp
apparatus in open capillary tubes and are uncorrected. IR spectra
were obtained using an FTIR Perkin–Elmer 1600 Infrared Spectro-
photometer. Only noteworthy IR absorptions are listed (cmꢁ1). 1H
and 13C NMR spectra were recorded on a Varian Gemini-200 (200
and 50.3 MHz, respectively) or Varian Gemini-300 (300 and
75.5 MHz) Instrument using CDCl3 as solvent with tetramethylsi-
lane as internal standard or (CD3)2CO. Other 1H NMR and
heterocorrelation 1H–13C (HMQC and HMBC) spectra were recor-
ded on a Varian VXR-500 (500 MHz). Mass spectra were recorded
on a Hewlett–Packard 5988-A. Column chromatography was per-
formed with silica gel (E. Merck, 70–230 mesh). Reactions were
monitored by TLC using 0.25 mm silica gel F-254 (E. Merck).
Microanalysis was determined on a Carlo Erba-1106 analyzer. All
reagents were of commercial quality or were purified before use.
Organic solvents were of analytical grade or were purified by
standard procedures. Commercial products were purchased from
Sigma–Aldrich.
The benzodioxino-isoquinoline 16 proved to be the most active
compound (IC50¼4ꢀ10ꢁ7 M). Weak cytotoxicity was observed for
the carboxylic acid 20 and also for the carbamates 21–23.
Table 1
Cytotoxic activity of compounds 14, 16 and 18–23a
Compound
R
D
IC50 L1210 Cellular cycle
b
(
mM)
(L1210
)
14
16
H
d
Tetrahydro
Aromatic
4
0.4
Tox G2M 38% 10 mM
49% 8 N, 0.5
G2M 10
G2M 78% 10
m
M
M
m
M
18
19
20
21
22
23
–(CH2)2–N(CH2CH3)2 Tetrahydro
8
6
m
–(CH2)5–COOCH3
–(CH2)5–COOH
Benzyl
Allyl
Propargyl
Tetrahydro
G1 68% 25
n.t.
mM
Tetrahydro >10
Tetrahydro 31
Tetrahydro 23
Tetrahydro 19
3.2. 2-Cyano-1,4-dimethyldibenzo[b,e][1,4]dioxin (3)
G2M 45% 25
G2M 50% 20
G2M 87% 20
m
m
m
M
M
M
An oven-dried flask equipped with a magnetic stirring bar was
charged with acrylonitrile (838 mg, 15.5 mmol) and isobenzofuran
18 (620 mg, 3.1 mmol) without solvent. The reaction mixture was
heated at 80 ꢂC for 60 h after which the mixture was cooled to room
temperature, the acrylonitrile was removed, and the crude of the
reaction was dissolved in 5 mL of THF. Then potassium tert-
butoxide (379 mg, 3.1 mmol) was added and the reaction mixture
was stirred at room temperature for 30 min. The crude material
was extracted with ether (3ꢀ20 mL), dried, filtered, and
Adriamycin
Ellipticine
0.029
0.19
G2M 86% 1
G2 50% 1
mM
M
m
a
Inhibition of L1210 cell proliferation measured by in vitro biological assay. IC50
values are mean concentrations that inhibit growth by 50%. (IC50 values are the
average of at least four determinations in triplicate obtained in independent ex-
periments. Variation between replicates was less than 5%.)
b
Percentage of L1210 cells arrested in cell cycle phase after 24 h of exposure to the
indicated concentration of problem compound (n.t.) not tested (considered not in-
teresting due to poor activity on L1210 cell lines).

M. Romero et al. / Tetrahedron 64 (2008) 11020–11027
11023
concentrated under vacuo. The residue was purified by silica gel
column chromatography (hexane/ethyl acetate in a ratio 9/1). The
title compound was isolated as a white solid (677 mg, 2.9 mmol,
(431 mg, 1.80 mmol) in THF (5 mL) was added and then stirring was
continued until the mixture reached room temperature (4 h). Then
a saturated solution of NH4Cl (5 mL) was added and the mixture
was extracted with ether (3ꢀ15 mL). The organic layers were dried
(Na2SO4), filtered, and the solvent evaporated to dryness under
vacuo. The residue was subjected to column chromatography on
silica gel (hexane/ethyl acetate in a ratio 6/4) to afford 385 mg
93% yield). Mp: 143–144 ꢂC (hexane/ethyl acetate). IR (KBr)
n
(cmꢁ1): 2202 (C^N), 1602 (C]C), 1260 (C–O–C). NMR 1H (CDCl3,
300 MHz) (ppm): 2.22 (s, 3H, CH3C4), 2.38 (s, 3H, CH3C1), 6.80–
6.97 (m, 4H, C6H, C7H, C8H, and C9H), 7.03 (s, 1H, C3H). NMR 13C
(CDCl3, 50.3 MHz) (ppm): 13.4 (CH3, CH3C1), 14.8 (CH3, CH3C4),
d
d
(1.28 mmol) of 6 as a white solid (71% yield). IR (KBr) n
(cmꢁ1):
107.3 (C, C2), 116.3 (CH, C6H, and C9H), 117.7 (C, CN), 123.0 (C, C4),
124.2 and 124.4 (CH, C7H, and C8H), 127.0 (C, C1), 129.0 (CH, C3H),
140.3 (C, C10a), 141.1, 141.3 (C, C5a, and C9a), 143.9 (C, C4a). MS (CI/
NH3), m/z: 255 (Mþ18), 238 (Mþ1). Anal. Calcd for C15H11NO2: C
75.94%; H 4.67%; N 5.90%. Found: C 75.56%; H 4.89%; N 5.89%.
3400–3100 (OH), 2936 (C–H), 1545 (NO2 st asymmetric), 1329 (NO2
st symmetric), 1258 (Ar–O), 1080 (C–O). NMR 1H (CDCl3, 300 MHz)
d
(ppm): 2.21 (s, 6H, CH3–), 4.41 (dd, J¼13.5, J0¼2.9, 1H, CH2NO2),
4.52 (dd, J¼13.5, J0¼9.5, 1H, CH2NO2), 5.57 (dd, J¼9.5, J ¼2.9, 1H,
0 0
CHOH), 6.83–6.90 (m, 4H, C6H, C7H, C8H, C9H), 6.91 (s, 1H, C3H).
NMR 13C (CDCl3, 75.5 MHz)
d (ppm): 10.3 (CH3, CH3C1), 15.1 (CH3,
3.3. 2-Formyl-1,4-dimethyldibenzo[b,e][1,4]dioxin (4)
CH3C4), 67.7 (CH, CHOH), 80.2 (CH2, CH2–NO2), 116.2 (CH, C6H,
C9H), 120.1 (C, C1, C4), 122.0 (CH, C3H), 123.3 (CH, C7H, C8H), 130.9
(C, C2), 140.1 and 140.4 (C, C4a, C10a), 142.1 (C, C5a, C9a). MS (EI),
m/z: 301 (Mþ, 52), 240 (MþꢁCH2NO2, 100), 212 (80), 198 (37), 77
(MþꢁC6H5þ, 48).
A solution of the nitril 3 (100 mg, 0.42 mmol) in 10 mL of dry
toluene was added to a stirred solution of 1 M DIBAL (0.42 mL,
0.42 mmol) under argon atmosphere. The reaction mixture was
stirred at room temperature for 5 min and then 5 N HCl (2 mL) was
slowly added. Immediately, the residue was extracted with ether
(3ꢀ10 mL), dried over Na2SO4, filtered, and the solvent was re-
moved under vacuo. The crude product was purified by silica gel
column chromatography (hexane/ethyl acetate in a ratio 9/1) giving
the title compound 4 (89 mg, 0.37 mmol, 88% yield) as a yellow
3.6. 1,4-Dimethyl-2-(1-hydroxy-2-amino-
ethyl)dibenzo[b,e][1,4]dioxin (7)
A suspension of compound 6 (380 mg, 1.26 mmol) and 10% Pd/C
(3.8 mg) in methanol (20 mL) was stirred at room temperature
under an atmosphere of hydrogen for 12 h. The catalyst was filtered
and the solvent was removed under vacuo. The residue was puri-
fied by column chromatography (on silica gel, hexane/ethyl acetate
in a ratio 7/3) giving 328 mg (1.20 mmol) of the amine 7 with 96%
solid. Mp: 254–256 ꢂC (hexane/ethyl acetate). IR (KBr)
2850 (C–H), 1682 (C]O), 1597, 1259 (C–O–C). NMR 1H (CDCl3,
200 MHz) (ppm): 2.24 (s, 3H, CH3C4), 2.50 (s, 3H, CH3C1), 6.81–
6.92 (m, 4H, C6H, C7H, C8H, and C9H), 7.22 (s, 1H, C3H), 9.98 (s, 1H,
CHO). NMR 13C (CDCl3, 50.3 MHz)
(ppm): 9.9 (CH3, CH3C1), 14.8
n
(cmꢁ1):
d
d
yield. IR (KBr)
n
(cmꢁ1): 3420–3080 (OH, NH), 2945 (C–H), 1224
(ppm): 2.13 and
(CH3, CH3C4), 116.2 (CH, C6H, and C9H), 123.8 and 124.2 (CH, C7H,
and C8H), 126.0 (C, C1, and C4), 128.9 (C, C2), 129.4 (CH, C3H), 140.0,
141.1, 141.4 (C, C4a, C5a, C9a, and C10a), 191.0 (CH, CHO). MS (CI/
NH3), m/z: 241 (Mþ1).
(Ar–O), 1108 (C–O). NMR 1H (CDCl3, 200 MHz)
d
2.15 (s, 6H, CH3C4 and CH3C1, respectively), 3.15–3.32 (s, 2H,
CH2NH2), 4.76–4.83 (m, 1H, CHOH), 6.75–6.80 (m, 4H, C6H, C7H,
C8H, C9H), 6.83 (s, 1H, C3H). This compound was treated directly
with the trimethoxybenzoic acid to give the amide 15.
3.4. 2-Hydroxymethyl-1,4-dimethyldibenzo[b,e][1,4]-
dioxin (5)
3.7. 2-Aminomethyl-1,4-dimethyldibenzo[b,e][1,4]dioxin (8)
NaBH4 (101 mg, 2.70 mmol) was slowly added to a solution of
the aldehyde 4 (581 mg, 2.40 mmol) in 8.50 mL methanol under
an inert atmosphere at 0 ꢂC. The mixture was stirred at room
temperature for 30 min. Then a solution of 2 N HCl (10 mL) was
added and methanol was removed under vacuo. The residue was
extracted with CH2Cl2 (3ꢀ15 mL), the combined organic solution
was dried, filtered, and evaporated giving the corresponding
alcohol. The resulting residue was purified by column chroma-
tography on silica gel (hexane/ethyl acetate in a ratio 7/3) to
afford as a white solid 555 mg (2.29 mmol) of the alcohol 5 (95%
A suspension of compound 3 (300 mg, 1.26 mmol) and PtO2
(30 mg) in methanol (20 mL) was stirred at room temperature
under an atmosphere of hydrogen for 12 h. The catalyst was filtered
and the solvent was removed under vacuo. The residue was puri-
fied by column chromatography (on silica gel, hexane/ethyl acetate
in a ratio 5/5) giving 301 mg (1.24 mmol) of the amine 8 with 99%
yield as a dense oil. IR (KBr)
n
(cmꢁ1): 3318 (NH), 1598, 1491, 1257
(ppm): 2.19, 2.20 (s, 6H, CH3C1
(Ar–O). NMR 1H (CDCl3, 300 MHz)
d
and CH3C4), 3.73 (s, 2H, CH2NH2), 6.70 (s, 1H, C3H), 6.80–6.97 (m,
4H, C6H, C7H, C8H, C9H). NMR 13C (CDCl3þCD3OD, 75.5 MHz)
yield). Mp: 156–157 ꢂC (hexane/ethyl acetate). IR (KBr)
3262 (OH), 2922 (C–H), 1600 (C]C), 1261 (Ar–O), 1080 (C–O).
NMR 1H (CDCl3, 200 MHz)
(ppm): 2.21 (s, 6H, CH3Cl, CH3C4),
4.57 (d, J¼2.8, 2H, CH2OH), 6.74 (s, 1H, C3H), 6.80–6.91 (m, 4H,
C6H, C7H, C8H, C9H). NMR 13C (CDCl3, 50.3 MHz)
(ppm): 63.9
n
(cmꢁ1):
d (ppm): 14.3 (CH3, CH3C1), 14.9 (CH3, CH3C4), 42.5 (CH, CH2N),
117.2 (CH, C6H, C9H), 120.8 (C, C2), 121.9 (C, C1, C4), 122.8 (CH, C7H,
C8H), 124.2 (CH, C3H), 139.4 and 140.6 (C, C4a, C10a), 141.6 (C, C5a,
C9a). Anal. Calcd for C15H15NO2: C 74.67%; H 6.27%; N 5.81%. Found:
C 74.96%; H 6.58%; N 5.48%.
d
d
(CH2, CH2OH), 116.9 (CH, C-6, C-9), 120.8 (C, C1), 122.1 (C, C4),
122.8 (C, C2), 124.0 (CH, C7H, and C8H), 124.6 (CH, C3H), 135.2 (C,
C4a), 140.2 (C, C10a), 141.1 (C, C5a), 192.2 (C, C9a). MS (CI/NH3),
m/z: 243 (Mþ1). Anal. Calcd for C15H14O3: C 74.36%; H 5.82%.
Found: C 74.12%; H 6.20%.
3.8. 2-Chloromethyl-1,4-dimethyldibenzo[b,e][1,4]dioxin (9)
To a solution of the alcohol 5 (503 mg, 2.10 mmol) in toluene
(30 mL) was added 2 mL (27 mmol) of SOCl2. The mixture was
stirred and heated at 120 ꢂC for 15 min. Then, the solvent was
removed and a solution of 0.1 N of NaHCO3 was added and the
reaction mixture was extracted with ether (3ꢀ10 mL). The com-
bined organic layers were washed with a solution of 0.1 N NaOH
several times and finally dried, filtered, and the solvent removed
under vacuo. The crude reaction mixture was purified by column
chromatography (on silica gel hexane/ethyl acetate in a ratio 8/2) to
give 471 mg (1.81 mmol) of 9 as a yellow solid (87% yield). Mp: 125–
3.5. 1,4-Dimethyl-2-(1-hydroxy-2-nitroethyl)-
dibenzo[b,e][1,4]dioxin (6)
To a solution of nitromethane (121 mg, 1.98 mmol) in dry THF
(15 mL) under argon was added a solution of 1.6 M of n-butyl
lithium in hexane (1.3 mL, 2.08 mmol) at ꢁ78 ꢂC and the reaction
mixture was stirred at this temperature for 30 min. A solution of 4

11024
M. Romero et al. / Tetrahedron 64 (2008) 11020–11027
127 ꢂC (hexane/ethyl acetate). IR (KBr)
n
(cmꢁ1): 2921 (C–H), 1599
(ppm): 2.19, 2.26
purified by column chromatography (on silica gel, hexane/ethyl
acetate in a ratio 5/5) giving 388 mg (1.52 mmol) of the amine 11 in
(C]C), 1256 (C–O–C). NMR 1H (CDCl3, 200 MHz)
d
(s, 6H, CH3C1, CH3C4), 4.51 (s, 2H, CH2Cl), 6.74 (s, 1H, C3H), 6.85–
95% yield.
6.93 (m, 4H, C6H, C7H, C8H, C9H). NMR 13C (CDCl3, 50.3 MHz)
d
(ppm): 10.6 (CH3, CH3C1), 14.9 (CH3, CH3C4), 44.9 (CH2, CH2Cl),
3.11. 1,4-Dimethyl-2-(2-(30,50,60-trimethoxybenzyl-
116.1, 116.2 (CH, C6H, C9H), 122.7 (C, C1), 122.9 (C, C4), 123.6, 123.7
(CH, C7H, C8H), 126.2 (CH, C3H), 130.4 (C, C2), 140.3, 140.6 (C, C4a,
C10a), 141.9, 142.0 (C, C5a, C9a). Anal. Calcd for C15H13ClO2: C
69.10%; H 5.03%. Found: C 68.79%; H 5.34%.
imine)ethyl)dibenzo[b,e][1,4]dioxin (12)
To a solution of the amine 11 (453 mg, 1.8 mmol) in 45 mL of dry
toluene was added 3,4,5-trimethoxybenzaldehyde (383 mg,
1.95 mmol), a catalytic amount of PTSA (p-toluenesulfonic acid),
and 80 mg of molecular sieves of 4 Å. The mixture was vigorously
stirred at reflux temperature for 12 h. Finally, the crude product
was filtered and the solvent removed under reduced pressure
affording 12 (730 mg, 1.69 mmol, 95% yield) as a colorless oil. NMR
3.9. 2-Cyanomethyl-1,4-dimethyldibenzo[b,e][1,4]dioxin (10)
The chloro derivative 9 (511 mg, 2.0 mmol) was dissolved in
DMF (3 mL), then HMPT (1 mL) and 255 mg (3.92 mmol) of KCN
were added and the resulting mixture was stirred at room tem-
perature for 12 h (reaction mixture was connected externally with
a 30% solution of KOH). Then a solution of 0.1 N of NaHCO3 (15 mL)
was added and the reaction mixture was extracted with ether
(3ꢀ10 mL). The combined organic layers were washed with water
several times and finally dried over Na2SO4, filtered, and the solvent
removed under vacuo. The crude product was purified by column
chromatography (on silica gel hexane/ethyl acetate in a ratio 7/3) to
give 399 mg (1.59 mmol, 81% yield) of the nitril 10 as a white solid.
1H (CDCl3, 200 MHz)
d (ppm): 2.15, 2.18 (s, 6H, CH3C1, CH3C4), 2.85
(t, J¼7.6, 2H, CH2CH2NH2), 2.85 (t, J¼7.6, 2H, CH2CH2NH2), 3.91 (s,
3H, CH3OC40H), 3.92 (s, 6H, CH3OC30, CH3OC50), 6.57 (s, 1H, C3H),
6.83–6.84 (m, 4H, C6H, C7H, C8H, C9H), 6.94 (s, 2H, C20H, C60H),
8.06 (s, 1H, CH]N). This compound was directly cyclized to the
isoquinoline 13.
3.12. 5,12-Dimethyl-2-trifluoroacetyl-1-(30,40,50-trimeth-
oxyphenyl)-1,2,3,4-tetrahydrobenzodioxino[2,3-
g]isoquinoline (13)
Mp: 161–164 ꢂC (hexane/ethyl acetate). IR (KBr)
H), 2238 (C^N), 1596 (C]C), 1256 (Ar–O), 1081 (C–O). NMR 1H
(CDCl3, 200 MHz) (ppm): 2.17, 2.20 (s, 6H, CH3C1, CH3C4), 3.53 (s,
2H, CH2CN), 6.74 (s, 1H, C3H), 6.80–6.91 (m, 4H, C6H, C7H, C8H,
C9H). NMR 13C (CDCl3, 50.3 MHz)
(ppm): 10.9 (CH3, CH3C1), 14.8
n
(cmꢁ1): 2931 (C–
d
The imine 12 (350 mg, 0.81 mmol) was dissolved in 1 mL
(7 mmol) of trifluoroacetic anhydride and 1 mL (13 mmol) of tri-
fluoroacetic acid was added. The resulting mixture was stirred at
room temperature for 12 h. Then the volatile reagents were dis-
tilled and the crude of reaction was purified by silica gel column
chromatography (hexane/ethyl acetate 6/4) giving the amide 13
d
(CH3, CH3C4), 21.4 (CH2, CH2CN), 116.2, 116.3 (CH, C6H, C9H), 117.5
(C, CN), 121.4 (C, C1), 123.1 (C, C4), 123.4 (C, C2), 123.4, 123.6 (CH,
C7H, C8H), 124.8 (CH, C3H), 140.3, 140.1, 140.4 (C, C4a, C10a), 141.8,
141.9 (C, C5a, C9a). Anal. Calcd for C16H13NO2: C 76.48%; H 5.21%; N
5.57%. Found: C 76.46%; H 4.97%; N 5.32%.
(282 mg, 0.57 mmol, 71% yield) as a colorless oil. IR (NaCl)
2938 (C–H), 1688 (C]O), 1592 (C]C), 1132 (Ar–O). NMR 1H (CDCl3,
200 MHz) (ppm): 1.93 (s, 3H, CH3C5), 2.16 (s, 3H, CH3C12), 2.72–
n
(cmꢁ1):
d
3.10. 2-(2-Aminoethyl)-1,4-dimethyldibenzo[b,e][1,4]-
dioxin (11)
2.93 (m, 2H, C–3H2), 3.29–3.52 (m, 2H, C–4H2), 3.76 (s, 6H,
CH3OC30, CH3OC50), 3.84 (s, 3H, CH3OC40), 6.41(s, 2H, C20H, C60H),
6.69 (s, 1H, C1H), 6.85–6.93 (m, 4H, C7H, C8H, C9H, C10H). NMR 13C
3.10.1. Method A
(CDCl3, 50.3 MHz) d (ppm): 10.8 (CH3, CH3C5, CH3C12), 27.0 (CH2,
A mixture of the nitroalcohol 6 (280 mg, 0.93 mmol) and P2O5
(264 mg, 1.86 mmol) in dry CH2Cl2 (10 mL) was stirred at room
temperature for 2 h. Then water (20 mL) was added and the
aqueous layer was extracted with CH2Cl2 (3ꢀ15 mL). The combined
organic extracts were dried and concentrated, and the resulting
residue was purified by column chromatography (hexane/ethyl
acetate 8/2) giving 171 mg (0.6 mmol, 65% yield) of the expected
intermediate olefin. A mixture of nitroolefines (125 mg, 0.44 mmol)
and Pd/C (12.5 mg, 10% w/w) in ethyl acetate (25 mL) was stirred at
room temperature under an atmosphere of hydrogen for 3 days.
The catalyst was filtered and the solvent was removed under vacuo
giving the amine 11 (69 mg, 0.27 mmol, 61% yield) as a colorless oil.
C3), 38.8 (CH2, C4), 54.7 (CH3, CH3OC40), 56.3 (CH3, CH3OC30,
CH3OC50), 60.8 (CH, C1), 105.7 (CH, C20H, C60H), 116.2 (CH, C7H,
C10H),116.6 (C, J¼288, CF3),121.0 (C, C5, C12),12306,12307 (CH, C8H,
C9H), 126.8, 127.2 (C, C4a, C12a), 135.4 (C, C10), 138.8, 139.4 (C, C5a,
C11a), 141.9, 142.0 (C, C6a, C10a), 153.3 (C, C30, C40, C50), 155.4 (C,
J¼35, C]O). Anal. Calcd for C28H26F3NO6: C 63.51%; H 4.95%; N
2.65%. Found: C 63.29%; H 5.33%; N 2.44%.
3.13. 5,12-Dimethyl-1-(30,40,5-trimethoxyphenyl)-1,2,3,4-
tetrahydrobenzodioxino[2,3-g]isoquinoline (14)
A solution of the amide 13 (451 mg 0.85 mmol) and 15 mL of 2 N
NaOH in 5 mL of methanol was stirred at room temperature for
12 h. The aqueous layer was extracted with ether (3ꢀ10 mL) and
then with dichloromethane (2ꢀ10 mL). The combined organic
layers were dried over anhydrous Na2SO4 and concentrated under
reduced pressure without an external heat source. The resulting
residue was purified via silica gel column chromatography. The
elution with a mixture of hexane/ethyl acetate in a ratio 1/9
afforded 342 mg (0.79 mmol, 86% yield) of the isoquinoline 14 as
IR (KBr)
n
(cmꢁ1): 3346 (NH), 1599 (C]C), 1257 (Ar–O), 1073 (C–O).
(ppm): 2.16 (s, 3H, CH3C1), 2.18 (s, 3H,
NMR 1H (CDCl3, 200 MHz)
d
CH3C4), 2.63 (t, J¼7, 2H, CH2CH2NH2), 2.86 (t, J¼7, 2H, CH2CH2NH2),
6.54 (s, 1H, C3H), 6.80–6.90 (m, 4H, C6H, C7H, C8H, C9H). NMR 13C
(CDCl3, 50.3 MHz)
d (ppm): 10.9 (CH3, CH3C1), 14.9 (CH3, CH3C4),
37.0 (CH2, CH2CH2NH2), 42.5 (CH2, CH2CH2NH2), 116.0, 116.1 (CH,
C6H, C9H), 121.4 (C, C1), 122.3 (C, C4), 123.3, 123.4 (CH, C7H, C8H),
125.5 (CH, C3H), 132.6 (C, C2), 138.1, 139.8 (C, C4a, C10a), 141.1, 142.2
(C, C5a, C9a). Anal. Calcd for C16H17NO2: C 75.27%; H 6.71%; N 5.49%.
Found: C 75.38%; H 6.99%; N 5.23%.
a yellow solid. Mp: 96–98 ꢂC (hexane/ethyl acetate). IR (KBr)
(cmꢁ1): 3446 (NH), 2932 (C–H), 1591 (C]C), 1253 (Ar–O), 1128 (C–
N). NMR 1H (CDCl3, 200 MHz)
(ppm): 1.82 (s, 3H, CH3C5), 2.15 (s,
n
d
3.10.2. Method B
3H, CH3C12), 2.45–2.65 (m, 2H, C–3H2), 2.81–2.97 (m, 2H, C–4H2),
3.78 (s, 6H, CH3OC30 and CH3OC50), 3.83 (s, 3H, CH3OC40), 5.03 (s,
1H, C1H), 6.34 (s, 2H, C20H and C60H), 6.81–6.89 (m, 4H, C7H, C8H,
A mixture of compound 10 (402 mg, 1.6 mmol) and PtO2 (40 mg,
10% w/w) in ethyl acetate (20 mL) was stirred at room temperature
under an atmosphere of hydrogen for 12 h. The catalyst was filtered
and the solvent was removed under vacuo. The residue was
C9H, C10H). NMR 13C (CDCl3, 50.3 MHz)
d
(ppm): 10.5, 10.6 (CH3,
CH3C5, CH3C12), 26.7 (CH2, C3), 37.4 (CH2, C4), 56.1 (CH3, CH3OC30,

M. Romero et al. / Tetrahedron 64 (2008) 11020–11027
11025
CH3OC50), 57.7 (CH3, CH3OC40), 60.7 (CH, C1H), 105.0 (CH, C20H,
C60H), 116.0 (CH, C7H, C10H), 120.3, 120.8 (C, C5, C12), 123.2, 123.3
(CH, C8H, C9H), 129.2 and 129.9 (C, C4a, C12a), 136.8 (C, C10), 138.6,
139.1 (C, C5a, C11a),142.1 (C, C6a, C10a),152.9 (C, C30, C40, C50). Anal.
Calcd for C26H27O5N: C 72.04%; H 6.28%; N 3.23%. Found: C 72.43%;
H 5.89%; N 2.89%.
(hexane/ethyl acetate in
a
ratio 5/5) yielding the dihy-
droisoquinoline 17 (61 mg, 0.14 mmol, 41% yield) as a colorless
oil and was recovered 74 mg (0.17 mmol) of the starting
compound.
To a solution of dihydroisoquinoline 17 (20 mg, 0.05 mmol) in
20 mL of anhydrous decahydronaphthalene (decalin solvent) 16 mg
of Pd/C 10% (0.02 mmol) were added. The reaction mixture was
refluxed (220 ꢂC) for 1 day. The mixture was filtered and the crude
product was distilled under reduced pressure (140 ꢂC, 0.01 mmHg).
Finally, the residue was purified by column chromatography (on
silica gel hexane/ethyl acetate in a ratio 5/5) to give the isoquinoline
16 (12 mg, 0.03 mmol, 55% yield) as a yellow solid.
3.14. 1,4-Dimethyl-2-(1-hydroxy-2-(30,40,5-trimethoxy-
benzamidoethyl))dibenzo[b,e][1,4]dioxin (15)
3,4,5-Trimethoxybenzoic acid (100 mg, 0.5 mmol) was dis-
solved in 20 mL of anhydrous toluene and SOCl2 (2 mL, 27 mmol)
was added. The resulting mixture was refluxed for 2 h, and then
cooled and the solvent was removed. Dichloromethane (20 mL)
and Et3N (128 mg, 0.5 mmol) were added to the crude of the re-
action. A solution of aminoalcohol 7 (128 mg, 0.5 mmol) was
added (using ice bath). The reaction mixture was stirred at room
temperature for 1 h. Finally, the solvent was removed and the
crude product was purified by column chromatography (silica gel,
hexane/ethyl acetate in a ratio 99/1) yielding 210 mg (0.45 mmol,
3.16. 5,12-Dimethyl-2-(diethylaminoethyl)-1-(30,40,50-
trimethoxyphenyl)-1,2,3,4-tetrahydrobenzodioxino[2,3-
g]isoquinoline (18)
To a solution of the amine 14 (80 mg, 0.18 mmol) in 16 mL of
recently distilled DMF were added 48 mg (0.36 mmol) of 2-chloro-
N,N-diethylamine hydrochloride, 62 mg (0.45 mmol) of anhydrous
K2CO3, and a catalytic amount of KI. The reaction mixture was
stirred under argon at room temperature for 7 days. After that
20 mL of water were added to the reaction mixture, organic
materials were extracted with ether (3ꢀ10 mL), and dried over
anhydrous Na2SO4. The organic phase was filtered and concen-
trated in vacuo, and the residue was purified by silica gel column
chromatography (ethyl acetate/methanol in a ratio 5/5) to afford
96% yield) of the amide 15 as a colorless oil. IR (KBr)
3226–3100 (C–H), 1626 (C]O), 1575 (N–C]O), 1243 (Ar–O), 1127
(C–O). NMR 1H (CDCl3, 200 MHz)
(ppm): 2.18 (s, 3H, CH3C1), 2.19
n
(cmꢁ1):
d
(s, 3H, CH3C4), 3.21–3.24 (m, 1H, CH2), 3.70–3.87 (m, 1H, CH2), 3.85
(s, 9H, CH3O), 5.05 (dd, J¼8.2, 2.8, 1H, CHOH), 6.80–6.90 (m, 4H,
C6H, C7H, C8H, C9H), 6.92 (s, 1H, C3H), 6.99 (s, 2H, C20H and C60H).
NMR 13C (CDCl3, 50.3 MHz)
d (ppm): 10.4 (CH3, CH3C1), 15.2 (CH3,
CH3C4), 46.9 (CH2, CH2–N), 56.3 (CH3, CH3OC30, and CH3OC50), 60.9
(CH3, CH3OC40), 70.1 (CH, CHOH), 104.3 (CH, C20H and C60H), 116.2
(CH, C6H, C9H), 120.2 (C, C1, C4), 121.6 (CH, C3H), 122.9 (CH, C7H,
C8H), 129.4 (C, C2), 134.5 (C, C10), 139.8 and 139.9 (C, C4a, C10a),
142.0 (C, C5a, C9a), 153.1 (C, C30, C40, C50), 168.2 (C, C]O). Anal.
Calcd for C26H27O7N: C 67.09%; H 5.85%; N 3.01%. Found: C 67.35%;
H 6.06%; N 2.78%.
amine 18 (62 mg, 0.11 mmol, 65% yield) as a colorless oil. IR (NaCl)
(cmꢁ1): 3326–3100 (NH, OH), 1626 (C]O), 1575 (N–C]O), 1243
(Ar–O), 1127 (C–O–C). NMR 1H (CDCl3, 200 MHz)
(ppm): 2.18, 2.19
n
d
(s, 6H –CH3), 3.21–3.38 (m, 1H, CH2–), 3.70–3.87 (m, 1H, CH2–), 3.85
(s, 9H, CH3O–), 5.05 (dd, J¼8.2, 2.8, 1H, CHOH), 6.80–6.90 (m, 4H,
C6H, C7H, C8H, C9H), 6.92 (s, 1H, H-3), 6.99 (s, 2H, H-20, H-60). NMR
13C (CDCl3, 50.3 MHz)
d (ppm): 10.4 (CH3), 15.2 (CH3), 46.9 (CH2,
CH2–N), 56.3 (CH3, CH3O– (ꢀ2)), 60.9 (CH3, CH3OC50), 70.1 (CH,
C1H), 104.3 (CH, C20H, and C60H), 116.2 (CH, C6H, and C9H), 120.2,
120.6 (C, C1, C4), 122.9 (CH, C7H, C8H), 129.4 (C, C2), 134.5 (C, C10),
139.8 and 139.9 (C, C4a, and C10a), 142.0 and 142.1 (C, C5a, and
C9a), 153.1 (C, C30, C40, and C50), 162.2 (C, C]O). Anal. Calcd for
C32H40N2O5: C 72.15%; H 7.57%; N 5.26%. Found: C 72.47%; H 7.87%;
N 4.91%.
3.15. 5,12-Dimethyl-1-(30,40,5-trimethoxyphenyl)-
benzodioxino[2,3-g]isoquinoline (16)
(a) The tetrahydroisoquinoline 14 (50 mg, 0.12 mmol) was dis-
solved in 20 mL of anhydrous decahydronaphthalene (decalinÒ
solvent) and then 40 mg of 10% Pd/C (0.04 mmol) was added.
The mixture was stirred at 220 ꢂC for 1 day. Finally, the sus-
pension was filtered and the residue was distilled under vacuo
(140 ꢂC, 0.01 mmHg). The crude product was purified by col-
umn chromatography (silica gel, hexane/ethyl acetate in a ratio
5/5) yielding 36 mg (0.08 mmol, 69% yield) of the isoquinoline
16 as a yellow solid. Mp: 225–228 ꢂC (hexane/ethyl acetate). IR
3.17. 5,12-Dimethyl-2-(methoxycarbonylpentyl)-1-(30,40,50-
trimethoxyphenyl)-1,2,3,4-tetrahydrobenzodioxino[2,3-
g]isoquinoline (19)
(KBr)
(CDCl3, 200 MHz)
n
(cmꢁ1): 2925 (C–H), 1270 (Ar–O), 1127 (C–O). NMR 1H
(ppm): 2.00 (s, 3H, CH3C5), 2.56 (s, 3H,
To a solution of the amine 14 (80 mg, 0.18 mmol) in 8 mL of
recently distilled DMF were added 48 mg (0.24 mmol) of methyl 6-
bromohexanoate, 62 mg (0.46 mmol) of anhydrous K2CO3, and
a catalytic amount of KI. The mixture was stirred under argon at
room temperature for 60 h. Water (20 mL) was added and the or-
ganic material was extracted with ether (3ꢀ10 mL). The combined
organic phases were dried over Na2SO4, filtered off, and concen-
trated in vacuo. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate in a ratio 5/5) to afford 19
d
CH3C12), 3.87 (s, 6H, CH3OC30 and CH3OC50), 3.91 (s, 3H,
CH3OC40), 6.67 (s, 2H, C20H and C60H), 6.81–6.94 (m, 4H, C7H,
C8H, C9H, and C10H), 7.60 (d, J¼5.8,1H, C4H), 8.42 (d, J¼5.8,1H,
C3H). NMR 13C (CDCl3, 50.3 MHz)
d (ppm): 10.3 (CH3, CH3C12),
15.1 (CH3, CH3C5), 56.2 (CH3, CH3OC30, and CH3OC50), 61.0 (CH3,
CH3OC40), 106.1 (CH, C20H, and C60H), 115.8 (CH, C4H), 116.2 and
116.3 (CH, C7H, and C10H), 118.8 (C, C12), 123.6(C, C12a), 123.7
and 123.9 (CH, C8H, and C9H), 124.3 (C, C5),135.5 (C, C4a),137.9
(68 mg, 0.12 mmol, 67% yield) as a colorless oil. IR (NaCl)
2933 (C–H), 1736 (C]O), 1262 (Ar–O), 1127 (C–O). NMR 1H (CDCl3,
200 MHz) (ppm): 1.25–1.47 (m, 2H, (CH2)2CH2(CH2)2CO2CH3),
n
(cmꢁ1):
(C, C10), 140.2 (CH, C3H), 140.8 (C, C11a), 141.1 (C, C5a), 141.3
(C,
*
C10a), 141.9
*
(C, C6a), 153.0 (C, C30, C40, and C50), 159.1 (C, C1);
d
*Interchangeable. Anal. Calcd for C26H23O5N: C 72.71%; H 5.40%;
N 3.26%. Found: C 72.97%; H 5.28%; N 2.84%.
1.55–1.76 (m, 4H, CH2CH2CH2CH2CH2CO2CH3), 1.86 (s, 3H, CH3C5),
2.16 (s, 3H, CH3C12), 2.32 (t, J¼7.4, 2H, (CH2)4CH2CO2CH3), 2.40–2.46
(m, 2H, CH2(CH2)4CO2CH3), 2.46–2.93 (m, 4H, C–3H2, C–4H2), 3.66 (s,
3H, CO2CH3), 3.76 (s, 6H, CH3OC30 and CH3OC50), 3.82 (s, 3H,
CH3OC40), 4.74 (s,1H, C1H), 6.30 (s, 2H, C20Hand C60H), 6.83–6.91 (m,
(b) The tetrahydroisoquinoline 14 (150 mg, 0.35 mmol) was dis-
solved in 40 mL of dry dichloromethane and Ag2O (21 mg,
1.4 mmol) was added slowly. The resulting mixture was
refluxed for 7 days. The solvent was removed under vacuo and
the residue was purified by silica gel column chromatography
4H, C7H, C8H, C9H, C10H). NMR 13C (CDCl3, 50.3 MHz)
10.5 (CH3, CH3C5, and CH3C12), 22.7 (CH2, (CH2)2CH2(CH2)2CO2CH3),
d (ppm): 10.4,

11026
M. Romero et al. / Tetrahedron 64 (2008) 11020–11027
24.9 (CH2, (CH2)3CH2CH2CO2CH3), 27.0 (CH2, CH2CH2(CH2)3CO2CH3),
27.8 (CH2, C–3H2), 34.1 (CH2, (CH2)4CH2CO2CH3), 41.8 (CH2, C–4H2),
51.5 (CH3, (CH2)5CO2CH3), 52.8 (CH3, CH3OC30), 56.1 (CH3, CH3OC40),
60.8 (CH3, CH3C50), 62.7 (CH, C1H), 106.7 (CH, C20H, and C60H), 116.0
(CH, C7H, and C10H), 120.7 and 120.9 (C, C5, and C12), 123.2 and
123.3 (CH, C8H, C9H),128.4,129.2 (C, C4a, C12a),136.8 (C, C10),138.7,
139.2 (C, C5a, C11a),142.2 and 142.3 (C, C6a, C10a),152.5 (C, C30, C40,
C50),174.0 (C, CO2CH3). Anal. Calcd for C33H39O7N: C 70.56%; H 7.00%;
N 2.49%. Found: C 70.33%; H 7.09%; N 2.53%.
3.20. 2-(2-Propenyloxycarbonylaminomethyl)-1,4-
dimethyldibenzo[b,e][1,4]dioxin (22)
The amine 8 (85 mg, 0.35 mmol) was dissolved in 15 mL of an-
hydrous dichloromethane and cooled to 0 ꢂC. Then triethylamine
(0.4 mL, 2.8 mmol) and allyl chloroformate (57 mg, 0.42 mmol)
were added and the mixture was stirred at room temperature for
30 min. The solvent was removed under vacuo and the crude of
reaction was purified by silica gel column chromatography. Using
hexane/ethyl acetate in a ratio 7/3 the carbamate 22 (94 mg,
0.29 mmol, 83% yield) was obtained as a white solid. Mp: 118–
3.18. 5,12-Dimethyl-2-carboxypentyl-1-(30,40,50-trimeth-
oxyphenyl)-1,2,3,4-tetrahydrobenzodioxino[2,3-
g]isoquinoline (20)
120 ꢂC (hexane/ethyl acetate). IR (KBr)
(C–H), 1682 (C]O), 1259 (Ar–O), 1079 (C–O). NMR 1H (CDCl3,
200 MHz) (ppm): 2.10 and 2.18 (s, 6H, CH3C1 and CH3C4), 4.16 (d,
n
(cmꢁ1): 3296 (NH), 2925
d
To a solution of the amino-ester 19 (40 mg, 0.07 mmol) in meth-
anol (10 mL) was added 10 mL of 2 N NaOH and the reaction mixture
was stirred at room temperature for 6 h. Then the mixture was neu-
tralizedbytheadditionof2 NHClandextractedwithether(3ꢀ10 mL)
and dichloromethane (2ꢀ10 mL). The combined organic phases were
dried over anhydrous Na2SO4, filtered, and the solvent removed in
vacuo. The crude of reaction was purified by silica gel column chro-
matography (ethyl acetate/methanol in a ratio 9/1) to afford the car-
boxylic acid 20 (36 mg, 0.07 mmol, 94% yield) as a colorless oil. IR
J¼6, 2H, CH2N), 4.57 (d, J¼5.6, 2H, CH2O), 4.94 (br s, 1H, NH), 5.21
(d, J¼10, 1Ha, CHCH2), 5.29 (dd, J¼17.0, J0¼1.4, 1Hb, CHCH2), 5.80–
6.00 (m, 1H, CHCH2), 6.58 (s, 1H, C3H), 6.83 (m, 4H, C6H, C7H, C8H
and C9H). NMR 13C (CDCl3, 50.3 MHz)
d (ppm): 10.5 (CH3, CH3C1),
14.9 (CH3, CH3C4), 42.8 (CH2, CH2N), 65.5 (CH2, CH2O), 116.0 (CH,
C6H, C9H), 117.5 (CH2, CHCH2), 121.4 (C, C1), 122.5 (C, C4), 123.4 (CH,
C7H, and C8H), 124.7 (CH, C3H), 130.7 (C, C2), 132.7 (CH, CHCH2),
139.4 and 139.9 (C, C4a, and C10a),141.8 and 141.9 (C, C5a, and C9a),
155.8 (C, C]O). Anal. Calcd for C19H19O4N: C 70.14%; H 5.89%; N
4.30%. Found: C 69.72%; H 5.46%; N 4.43%.
(NaCl)
n
(cmꢁ1): 3442 (OH), 2932 (C–H), 1714 (C]O), 1591 (C]C),
(ppm): 1.26–1.42 (m, 2H,
1128 (C–O). NMR 1H (CDCl3, 200 MHz)
d
(CH2)2CH2(CH2)2CO2H), 1.50–1.80 (m, 4H, CH2CH2CH2CH2CH2CO2H),
1.86 (s, 3H, CH3C5), 2.17 (s, 3H, CH3C12), 2.19 (m, 2H, (CH2)4CH2CO2H),
2.50–2.88 (m, 4H, C–3H2, C–4H2), 2.98–3.15 (m, 2H, CH2(CH2)4CO2H),
3.75 (s, 6H, CH3OC30 and CH3OC50), 3.82 (s, 3H, CH3OC40), 5.15 (s, 1H,
C1H), 6.40 (s, 2H, C20H and C60H), 6.79–6.92 (m, 4H, C7H, C8H, C9H,
3.21. 2-(2-Propynyloxycarbonylaminomethyl)-1,4-
dimethyldibenzo[b,e][1,4]dioxin (23)
The amine 8 (85 mg, 0.35 mmol) was dissolved in 15 mL of an-
hydrous dichloromethane and cooled to 0 ꢂC. Then triethylamine
(0.4 mL, 2.8 mmol) and propargyl chloroformate (50 mg,
0.42 mmol) were added and the mixture was stirred at room
temperature for 30 min. The solvent was removed under vacuo and
the crude of reaction was purified by silica gel column chroma-
tography. Using hexane/ethyl acetate in a ratio 7/3 the carbamate
23 (101 mg, 0.31 mmol, 89% yield) was obtained as a white solid.
and C10H). NMR 13C (CDCl3, 50.3 MHz)
d (ppm): 10.3 and 10.7 (CH3,
CH3C5, and CH3C12), 22.1 (CH2, (CH2)2CH2(CH2)2CO2H), 25.1 (CH2,
CH2CH2CH2CH2CH2CO2H), 26.0 (CH2, (CH2)4CH2CO2H), 26.7 (CH2, C–
3H2), 29.7 (CH2, CH2(CH2)4CO2H), 40.6 (CH2, C–4H2), 52.2 (CH3,
CH3OC40), 56.2 (CH3, CH3OC30, and CH3OC50), 60.8 (CH, C1H), 107.7
(CH,C20H, andC60H),116.1(CH, C7H, andC10H),120.7and121.0(C, C5,
and C12),123.4 and 123.5 (CH, C8H, and C9H),126.7 and 126.8 (C, C4a,
and C12a),137.7 (C, C10),138.7 and 139.3 (C, C5a, and C11a),142.0 and
142.1 (C, C6a, and C10a), 152.8 (C, C30, C40, and C50), 171.4 (C, C]O).
Anal. Calcd for C32H37O7N: C 70.18%; H 6.80%; N 2.55%. Found: C
70.32%; H 6.56%; N 2.29%.
Mp: 170–173 ꢂC (hexane/ethyl acetate). IR (KBr)
(NH), 3291 (C^CH st), 2280 (C^C st), 2925 (C–H), 1694 (C]O),
1257 (Ar–O), 1076 (C–O). NMR 1H (CDCl3, 200 MHz)
(ppm): 2.15
n
(cmꢁ1): 3307
d
and 2.18 (s, 6H, CH3C1 and CH3C4), 2.50 (s, 1H, C^CH), 4.23 (d,
J¼5.6, 2H, CH2N), 4.70 (s, 2H, CH2O), 5.21 (br s, 1H, NH), 6.64 (s, 1H,
C3H), 6.86 (m, 4H, C6H, C7H, C8H, C9H). NMR 13C (CDCl3, 50.3 MHz)
3.19. 2-(Benzyloxycarbonylaminomethyl)-1,4-
dimethyldibenzo[b,e][1,4]dioxin (21)
d
(ppm): 10.5 (CH3, CH3C1), 14.9 (CH3, CH3C4), 43.0 (CH2, CH2N),
52.6 (CH2, CH2O), 74.6 (CH, C^CH), 116.1 (CH, C6H, C9H), 121.5 (C,
C1), 122.6 (C, C4), 123.5 (CH, C7H, C8H), 124.7 (CH, C3H), 130.4 (C,
C2), 139.6, 14001 (C, C4a, and C10a), 141.9 and 142.0 (C, C5a, C9a),
155.2 (C, C]O). Anal. Calcd for C19H17O4N: C 70.58%; H 5.30%; N
4.33%. Found: C 70.86%; H 5.51%; N 4.01%.
The amine 8 (30 mg, 0.12 mmol) was dissolved in 15 mL of an-
hydrous dichloromethane and cooled to 0 ꢂC. Then triethylamine
(0.2 mL, 1.4 mmol) and benzyl chloroformate (24 mg, 0.14 mmol)
were added and the mixture was stirred at room temperature for
30 min. The solvent was removed under vacuo and the crude of
reaction was purified by silica gel column chromatography. Using
hexane/ethyl acetate in a ratio 8/2 the carbamate 21 (43 mg,
0.11 mmol, 96% yield) was obtained as a white solid. Mp: 143–
3.22. Antitumor activities
The antitumor activity was realized by the laboratories Servier
(France) according to the method detailed before in our previous
work.9
145 ꢂC (hexane/ethyl acetate). IR (KBr)
(C–H), 1682 (C]O), 1257 (Ar–O), 1077 (C–O). NMR 1H (CDCl3,
200 MHz) (ppm): 2.16 and 2.20 (s, 6H, CH3C1 and CH3C4), 4.26 (d,
n
(cmꢁ1): 3302 (NH), 2921
d
J¼5.6, 2H, CH2N), 4.84 (br s, 1H, NH), 5.13 (s, 2H, CH2O), 6.64 (s, 1H,
Acknowledgements
C3H), 6.87 (m, 4H, C6H, C7H, C8H, C9H), 7.36 (m, 5H, C20H, C30H,
C40H, C50H, C60H). NMR 13C (CDCl3, 50.3 MHz)
d (ppm): 10.6 (CH3,
Financial support by the Spanish CICYT (CTQ2007-60614/BQU),
Generalitat (2005-SER-00180) and the Laboratories Servier (France)
is gratefully acknowledged.
CH3C1), 14.9 (CH3, CH3C4), 42.9 (CH2, CH2N), 66.7 (CH2, CH2O),116.1
(CH, C6H, C9H), 121.5 (C, C1), 122.6 (C, C4), 123.5 (CH, C7H, C8H),
124.7 (CH, C3H), 128.1 (CH, C40H), 128.4 (CH, C20H, and C60H), 128.5
(CH, C30H, and C50H), 130.8 (C, C2), 136.5 (C, C10), 139.9 and 140.0 (C,
C4a, and C10a), 141.9 and 142.0 (C, C5a, and C9a), 156.1 (C, C]O).
Anal. Calcd for C23H21O4N: C 73.58%; H 5.64%; N 3.73%. Found: C
73.78%; H 5.63%; N 3.49%.
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