Iodine-catalyzed aza-prins cyclization: Metal-free synthesis and antiproliferative activity of hexahydrobenzo[f]isoquinolines

Article abstract of DOI:10.1055/s-0032-1318478

A series of hexahydrobenzo[f]isoquinolines were synthesized by an iodine-catalyzed aza-Prins cyclization under metal-free conditions. An aliphatic or an aromatic aldehyde can be used as the carbonyl component in this reaction, which can also be performed efficiently under solvent-free conditions. During this study, we discovered new compounds with moderate antitumor activities. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0032-1318478

1076▌
PAPER
paper
Iodine-Catalyzed Aza-Prins Cyclization: Metal-Free Synthesis and
Antiproliferative Activity of Hexahydrobenzo[f]isoquinolines
Synthesis and Antiproliferative Activity of Hexahydrobenzo[f]isoquinolines
Carlos A. M. Figueiredo,a K. R. Kishore K. Reddy,a Paula A. Monteiro,b João E. de Carvalho,b Ana L. T. G. Ruiz,b
Luiz F. Silva, Jr*a
a
Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, CP 26077, CEP 05513-970 São Paulo SP, Brazil
Fax +55(128)155579; E-mail: luizfsjr@iq.usp.br
b
Divisão de Farmacologia e Toxicologia, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas (CPQBA), UNICAMP,
CP6171, 13083-970 Campinas, SP, Brazil
Received: 30.01.2013; Accepted after revision: 25.02.2013
were lower, although still within the practical range (en-
Abstract: A series of hexahydrobenzo[f]isoquinolines were syn-
tries 4 and 5). We also performed the reaction with aro-
thesized by an iodine-catalyzed aza-Prins cyclization under metal-
matic aldehydes, including aldehydes substituted with
electron-withdrawing and or electron-donating groups,
free conditions. An aliphatic or an aromatic aldehyde can be used as
the carbonyl component in this reaction, which can also be per-
formed efficiently under solvent-free conditions. During this study, and the reaction times in these cases were as much as three
we discovered new compounds with moderate antitumor activities.
days (entries 6–8). The nitro-substituted aldehyde 2h gave
a low yield of the corresponding product (entry 8). We
also investigated the behavior of cinnamaldehyde (2i) in
the aza-Prins reaction with 1, and we found that it gave the
desired product 3i in very good yield (entry 9).
Key words: cyclizations, iodine, catalysis, heterocycles, amines,
aldehydes, antitumor agents
Aza-Prins cyclization can be defined as the reaction of a
homoallylic amine with a carbonyl compound in the pres-
ence of an acid (Lewis or Brønsted). This reaction pro-
vides a powerful method for the synthesis of N-
heterocycles.1,2 Thus, preparations of piperidines and tet-
rahydropyridines by a wide range of protocols have been
reported.3–18 However, aza-Prins reactions have been used
less frequently in the construction of other ring systems.19–23
In this context, we describe the synthesis under mild and
metal-free conditions of a series of hexahydrobenzo[f]iso-
quinolines through an iodine-catalyzed aza-Prins cycliza-
tion. On the basis of the potential biological activity of the
target compounds24–26 and our continuing efforts to dis-
cover new antitumor entities,27,28 we also examined the
antiproliferative activities of the hexahydrobenzo[f]iso-
quinolines that we prepared.
The reaction time for some of the reactions shown in Ta-
ble 1 was relatively long (>24 hours). With solvent-free
conditions and higher temperatures, it was possible to iso-
late the desired N-heterocyclic compounds in shorter re-
action times and in comparable or higher yields (compare
Table 2 with entries 7 and 8 in Table 1).
The relative configurations of compounds 3b–i were as-
signed by NMR analysis, including NOESY experiments.
The preferential formation of the trans-diastereomer of
the hexahydrobenzo[f]isoquinolines 3 can be explained in
terms of the mechanism of the reaction (Scheme 1).32 The
reaction of the homoallylic amine 1 with aldehyde 2 cata-
lyzed by the Lewis acid iodine gives the iminium ion 4.
This intermediate can lead to the final product trans-3
through (E)-4 or to cis-3 through (Z)-4. Steric interactions
should favor the pathway through (E)-4. This mechanism
also explains the lower reactivities and longer reaction
times of bulky aldehydes 2. During the reaction, hydrogen
iodide and hypoiodous acid (HOI) are formed. These spe-
cies react to form iodine and water, thereby explaining the
catalytic action of iodine.32 The diastereoselectivity of the
iodine-catalyzed aza-Prins cyclization of 1 contrasts with
that of the Prins cyclizations of the corresponding alco-
hols with the same aldehydes, which give the cis-diaste-
reomers preferentially.32
N-[2-(3,4-Dihydronaphthalen-1-yl)propyl]-4-methylben-
zenesulfonamide (1) was prepared from 1-tetralone in
four steps: Reformatsky/dehydration reaction, reduction,
Mitsunobu reaction, and hydrolysis of a tert-butoxycar-
bonyl group.29–31 A series of commercially available alde-
hydes were used as the carbonyl components. On the basis
of our previous works on Prins cyclization,32,33 we per-
formed the cyclizations by using 10 mol% of iodine as the
catalyst in dichloromethane (Table 1). When an unhin-
dered aliphatic aldehyde such as formaldehyde, acetalde-
hyde, or butanal was used as the carbonyl component, the
reaction was complete within 1.5–3 hours (entries 1–3).
For more-hindered aliphatic aldehydes, such as 2d–e, the
reaction time increased to one to two days, and yields
On the basis of the expected biological activity of hexahy-
drobenzo[f]isoquinolines 3, we evaluated their antiprolif-
erative activity toward human tumor cell lines and one
nontumor human cell line in vitro. The compounds were
tested at concentrations of 0.25–250 µg mL–1 with doxo-
rubicin (0.025–25 µg mL–1) as the positive control. The
concentration eliciting a 50% inhibition in growth (GI50)
was determined after 48 hours of cell treatment, and the
SYNTHESIS 2013, 45, 1076–1082
Advanced online publication: 13.03.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1318478; Art ID: SS-2013-M0088-OP
© Georg Thieme Verlag Stuttgart · New York

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Synthesis and Antiproliferative Activity of Hexahydrobenzo[f]isoquinolines
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relevant results are listed in Table 3. To analyze the GI50 pounds 3c (mean log GI50 = 1.0) and 3d (mean log GI50 <
parameter, we calculated the value of log GI50 from the 1.0) showed moderate activity. These results suggest that
GI50 value for each test compound against each tumor cell a lateral carbon chain is important to the antiproliferative
line tested (apart from the normal cell line HaCat), and effect. Alkyl groups, such as propyl (3c) or isopropyl (3d)
then we took the average of these values. According to are better substituents than aryl groups. When the aryl
National Cancer Institute (NCI/EUA), if the value of the group was substituted by an electron-withdrawing group
mean log GI50 is less than 1.50, the tested compound can (3h) or electron-donating group (3g), the compounds were
be considered to be active and can be classified as show- inactive. The compounds 3c and 3d showed similar mod-
ing weak (1.1 < mean log GI50 < 1.5), moderate (0 < mean erate activities; however, 3c was more active toward
log GI50 < 1.1) or potent (mean log GI50 < 0) activity.34 On K562 and NCI-ADR/RES, whereas 3d was more active
the basis of this criterion, compounds 3h, cis-3g and toward PC-3, OVCAR-3, and MCF-7. Compound trans-
trans-3g were considered to be inactive (mean log GI50 > 3g selectively inhibited the growth of NCI-ADR/RES,
1.5) (Table 3), whereas compound 3f showed a weak an- OVCAR-3, PC-3, and K562, whereas cis-3g was active
tiproliferative effect (mean log GI50 = 1.4), and com- against PC-3 and NCI-ADR/RES.
Table 1 Iodine-Catalyzed Aza-Prins Cyclization in Dichloromethane
NTs
NHTs
+
I2 (10 mol%)
CH2Cl2, r.t.
R
RCHO
1
2
3
Entry
1
Aldehyde
Time (h)
1.5
Product
Yielda (%)
63%
NTs
NTs
HCHO (2a)
3a
3b
3c
3d
3e
3f
2
3
4
5
6
MeCHO (2b)
PrCHO (2c)
i-PrCHO (2d)
CyCHO (2e)
PhCHO (2f)
3
3
75% (cis/trans 1:5)
76% (cis/trans 1:6)
50% (cis/trans 1:11)
54% (cis/trans 1:6)
64% (cis/trans 1:1.15)
NTs
NTs
NTs
NTs
24
48
5
© Georg Thieme Verlag Stuttgart · New York
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C. A. Figueiredo et al.
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Table 1 Iodine-Catalyzed Aza-Prins Cyclization in Dichloromethane (continued)
NTs
NHTs
+
I2 (10 mol%)
CH2Cl2, r.t.
R
RCHO
1
2
3
Entry
7
Aldehyde
Time (h)
72
Product
Yielda (%)
NTs
NTs
NTs
4-MeOC6H4CHO (2g)
56% (cis/trans 1:1)
OMe
3g
8
9
4-O2NC6H4CHO (2h)
72
24
28% (cis/trans 1:2)
75% (cis/trans 1:2.4)
NO2
3h
3i
Ph
(E)-PhCH=CHCHO (2i)
a Isolated yield.
Table 2 Iodine-Catalyzed Aza-Prins Cyclization under Solvent-Free Conditions
NTs
Ar
NHTs
+
I2 (10 mol%)
solvent-free
50–55 °C
ArCHO
1
2
3
Entry
1
Aldehyde
Time (h)
Product
Yielda (%)
NTs
4-MeOC6H4CHO (2g)
4-O2NC6H4CHO (2h)
6
55% (cis/trans 1:1)
OMe
3g
3h
NTs
2
4
41% (cis/trans 1:2)
NO2
a Isolated yield.
In conclusion, we accomplished a metal-free synthesis of tions. This protocol can be used to obtain other nitrogen
a series of hexahydrobenzo[f]isoquinolines 3 by means of heterocycles in an efficient manner. During this study, we
an iodine-catalyzed aza-Prins cyclization of a homoallylic also discovered new compounds that showed moderate
amine 1 with an aliphatic or aromatic aldehyde 2. The re- antitumor activity and good selectivity toward various tu-
action can also be performed under solvent-free condi- mor cell lines
Synthesis 2013, 45, 1076–1082
© Georg Thieme Verlag Stuttgart · New York

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Synthesis and Antiproliferative Activity of Hexahydrobenzo[f]isoquinolines
1079
Table 3 Antiproliferative Activities (GI50; μg·mL–1) of Hexahydrobenzo[f]isoquinolines 3
Cell linea
Controlb
3c
3d
3f
3h
cis-3g
trans-3g
(cis/trans 1:6) (cis/trans 1:10) (cis/trans 1:1.7) (cis/trans 1:2)
(cis/trans 1:6.2)
U251
0.025
<0.25
0.19
121.1
11.5
6.7
148.6
5.8
45.3
38.7
6.0
>250
>250
>250
29.9
10.6
61.3
>250
>250
1.8
>250
83.2
2.7
MCF-7
NCI-ADR/RES
OVCAR-3
786-0
10.1
19.6
0.031
0.025
<0.25
<0.25
0.37
4.1
0.58
15.8
>250
>250
>250
9.4
93.1
53.4
0.25
0.80
95.6
50.2
1.0 (M)
45.3
>250
56.3
>250
9.4
NCI-H460
PC-3
63.3
100.8
<0.25
20.1
<0.25
9.2
<0.25
0.38
>250
>250
>1.6 (I)
K562
231.2
38.2
>250
15.7
>250
>250
>1.6 (I)
HT-29
0.12
86.4
114.4
133.0
HaCat
0.068
<–0.9 (P)
63.4
c
Mean log GI50
<1.0 (M)
1.4 (W)
>1.7 (I)
a U251: glioma; MCF-7: breast; NCI-ADR/RES: ovarian resistant to multiple drugs; OVCAR-3: ovarian; 786-0: kidney; NCI-H460: lung, non-
small cells; PC-3: prostate; K562: leukemia; HT-29: colon; HaCat: human keratinocyte, immortalized normal cell.
b Doxorubicin.
c NCI criteria: mean log GI50 > 1.50 = inactive (I); 1.1 < mean log GI50 < 1.5 = weak activity (W); 0 < mean log GI50 < 1.1 = moderate activity
(M); mean log GI50 < 0 = potent activity (P).34
N-[2-(3,4-Dihydronaphthalen-1-yl)propyl]-4-methylbenzene-
sulfonamide (1)
‡
NTs
Me
PPh3 (1.11 g, 4.23 mmol) and 2-(3,4-dihydronaphthalen-1-yl)pro-
pan-1-ol29 (0.795 g, 4.23 mmol) were added to a stirred soln of
TsNHBoc30,31 (1.18 g, 4.23 mmol) in anhyd THF (9.4 mL). The
mixture was cooled to 0 °C and DIAD (0.84 g, 4.2 mmol) was add-
ed. After 5 min, the mixture was warmed to r.t. for 1 h. The solvent
was then removed under reduced pressure and the residue was puri-
fied by flash chromatography (30% EtOAc–hexanes) to give the in-
termediate tert-butoxycarbonyl derivative; yield: 1.36 g (3.06
mmol, 72%).
δ+
δ+
H
– H+
R
R
H
I2 (cat.)
RCHO
N
trans-3
Ts
1
(E)-4
‡
Me
NTs
δ+
δ+
H
– H+
R
H
R
A stirred soln of this product (1.31 g, 2.96 mmol) in MeOH (30 mL)
was treated with K2CO3 (2.04, 14.8 mmol), and the mixture was
heated to 60 °C for 19 h. The mixture was then cooled to r.t. and
H2O (8 mL) was added. The aqueous phase was extracted with
EtOAc (2 × 10 mL). The organic phases were combined, washed
with brine, and dried (MgSO4). The solvent was removed under re-
duced pressure, and the residue was purified by flash chromatogra-
phy (20% EtOAc–hexanes) to give 1 as a highly viscous oil; yield:
0.722 g (2.11 mmol, 50%).
N
Ts
cis-3
(Z)-4
Scheme 1 Mechanism for the iodine-catalyzed aza-Prins cyclization
All commercially available reagents were used without further pu-
rification unless otherwise noted. All solvents used in reactions and
in chromatography were dried and purified by standard methods.
THF and benzene were freshly distilled over sodium/benzophe-
none. CH2Cl2 was freshly distilled over CaH2. TLC analyses were
performed by using plates coated with silica gel 60F 254. Spots
were detected by UV absorption (254 nm) or by spraying with 4- an-
isaldehyde and phosphomolybdic acid solutions and then charring
at ~150 °C. Flash column chromatography was performed on 200–
400 mesh silica gel. All NMR analyses were recorded on Bruker or
Varian spectrometers with CDCl3 as solvent and TMS as the internal
standard. Chemical shifts are reported relative to TMS with the sol-
vent as the internal standard. IR spectra were recorded on a Perkin-
Elmer 1750-FT spectrophotometer. Low-resolution mass spectra
were recorded on a Shimadzu 14B/QP5050A spectrometer, and
high-resolution mass spectra were recorded on a Bruker Daltonics
MicroTOF Electrospray spectrometer operating in the ESI mode.
IR (film): 3286, 1325, 1160, 551 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.13 (d, J = 6.6 Hz, 3 H), 2.21–
2.15 (m, 2 H), 2.36 (s, 3 H), 2.63 (t, J = 8.1 Hz, 2 H), 2.91–3.00 (m,
2 H), 3.07–3.13 (m, 1 H), 4.94–4.97 (m, 1 H), 5.78 (t, J = 4.5 Hz),
7.10–7.11 (m, 4 H), 7.18–7.21 (m, 2 H), 7.67–7.69 (m, 2 H).
13C NMR (50 MHz, CDCl3): δ = 17.7, 21.4, 22.8, 28.1, 33.5, 47.5,
121.9, 124.2, 126.3, 126.7, 126.8, 127.7, 129.5, 133.8, 136.7, 136.8,
137.6, 143.1.
LRMS: m/z (%) = 341 (2) [M+●], 186 (86), 91 (100).
HRMS (ESI): m/z calcd for [C20H23NO2S + Na]+: 364.1347; found:
364.1340.
1-Methyl-3-tosyl-1,2,3,4,5,6-hexahydrobenzo[f]isoquinoline
(3a); Typical Procedure
I2 (0.076 g, 0.030 mmol) was added to a stirred soln of 1 (0.10 g,
0.30 mmol) and 2a (0.011 mL, 0.36 mmol) in CH2Cl2 (1.1 mL), and
© Georg Thieme Verlag Stuttgart · New York
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C. A. Figueiredo et al.
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the mixture was stirred for 1.5 h at r.t. Na2SO3 (0.038 g, 0.30 mmol)
and H2O (10 mL) were then added, and the aqueous phase was ex-
tracted with EtOAc (3 × 5 mL). The organic phases were combined,
washed with brine (5 mL), dried (MgSO4), and concentrated under
reduced pressure. The crude product was purified by flash column
chromatography (20% EtOAc–hexanes) to give a colorless viscous
oil; yield: 0.068 g (0.19 mmol, 63%).
3.5 Hz, 1 H), 2.77 (dd, J = 15.2, 6.5 Hz, 1 H), 3.41 (dd, J = 13.5, 4.0
Hz, 1 H), 3.81 (d, J = 13.5 Hz, 1 H), 4.48 (t, J = 5.0 Hz, 1 H), 7.11–
7.13 (m, 2 H), 7.17–7.19 (m, 2 H), 7.26 (s, 1 H), 7.27 (s, 1 H), 7.75
(s, 1 H), 7.77 (s, 1 H); δ (cis-3c) = 0.86 (d, J = 7.0 Hz, 3 H), 1.00 (t,
J = 7.0 Hz, 3 H), 1.81–1.82 (m, 1 H), 1.85–1.93 (m, 2 H), 2.09–2.11
(m, 2 H), 2.14 (s, 3 H), 2.53 (dd, J = 16.2, 6.0 Hz, 1 H), 2.60 (ddd,
J = 15.0, 6.0, 2.0 Hz, 1 H), 2.82–2.84 (m, 1 H), 3.02 (dd, J = 15.0,
10.5 Hz, 1 H), 4.03 (ddd, J = 16.5, 7.5, 1.5 Hz, 1 H), 4.08–4.10 (m,
1 H), 6.54–6.55 (m, 1 H), 7.00 (d, J = 8.5 Hz, 1 H), 7.04 (d, J = 3.0
Hz, 2 H), 7.59 (d, J = 8.0 Hz, 2 H); other signals overlapped with
the major diastereomer.
13C NMR (75 MHz, CDCl3): δ (trans-3c) = 14.3, 18.9, 19.3, 21.4,
27.4, 28.2, 28.4, 34.5, 46.2, 57.4, 122.2, 126.4, 126.5, 127.1, 127.5,
129.4, 131.0, 132.3, 133.5, 136.2, 139.2, 142.8; δ (cis-3c) = 13.7,
18.7, 19.9, 21.2, 25.3, 27.0, 28.1, 35.0, 45.8, 57.3, 122.7, 125.5,
125.9, 126.8, 129.0, 131.2, 133.2, 135.0, 136.0, 137.7, 143.0; other
signals overlapped with the major diastereomer.
IR (film): 3057, 3014, 2930, 2887, 1597, 1490, 1457, 1449, 1336,
1161, 940, 811, 764, 671, 571, 549 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.26 (d, J = 6.6 Hz, 3 H), 2.03–
2.13 (m, 2 H), 2.42 (s, 3 H), 2.63–2.77 (m, 2 H), 2.82 (dd, J = 11.2,
3.6 Hz, 1 H), 2.91 (br s, 1 H), 3.30 (d, J = 16.8 Hz, 1 H), 3.52 (dd,
J = 11.1, 3.0 Hz, 1 H), 3.95 (d, J = 16.5 Hz, 1 H), 7.07–7.11 (m, 2
H), 7.17–7.19 (m, 2 H), 7.33 (d, J = 8.4 Hz, 2 H), 7.71 (d, J = 8.4
Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 18.5, 21.5, 26.1, 27.8, 29.1, 48.5,
49.9, 122.1, 126.4, 126.5, 127.7, 127.8, 127.9, 129.6, 130.9, 133.1,
133.2, 135.5, 143.5.
HRMS (ESI): m/z calcd for [C24H29NO2S + H]+: 396.1997; found:
396.1995.
LRMS: m/z (%) = 353 (9) [M+●], 198 (33), 196 (39), 182 (17), 171
(65), 155 (27), 153 (17), 143 (20), 141 (33), 129 (73), 128 (42), 127
(16), 115 (33), 91 (100).
4-Isopropyl-1-methyl-3-tosyl-1,2,3,4,5,6-hexahydrobenzo[f]iso-
quinoline (3d)
The reaction was performed by following the typical procedure, but
using 1 (0.12 g, 0.37 mmol), 2d (0.026 mL, 0.37 mmol), CH2Cl2
(1.4 mL), and I2 (0.0093 g, 0.037 mmol) to give a colorless viscous
oil: yield: 0.071 g (0.18 mmol, 50%; cis/trans = 1:11).
HRMS (ESI): m/z calcd for [C21H23NO2S + Na]+: 376.1347; found:
376.1348.
1,4-Dimethyl-3-tosyl-1,2,3,4,5,6-hexahydrobenzo[f]isoquino-
line (3b)
The reaction was performed by following the typical procedure, but
using 1 (0.14 g, 0.40 mmol), 2b (0.018 g, 0.40 mmol), CH2Cl2 (1.2
mL), and I2 (0.010 g, 0.040 mmol) to give a colorless viscous oil;
yield: 0.11 g (0.30 mmol, 75%; cis/trans = 1:5).
IR (film): 3063, 3025, 2965, 2930, 2875, 2832, 1598, 1489, 1469,
1453, 1378, 1335, 1151, 1090, 1027, 909, 814, 767, 677, 669, 594,
584 cm–1.
1H NMR (500 MHz, CDCl3): δ (trans-3d) = 0.73 (d, J = 7.0 Hz, 3
H), 0.90 (d, J = 7.0 Hz, 3 H), 0.94 (d, J = 7.0 Hz, 3 H), 2.00–2.08
(m, 1 H), 2.11 (t, J = 4.0 Hz, 3 H), 2.32 (ddd, J = 15.1, 6.5, 2.0 Hz,
1 H), 2.37 (s, 1 H), 2.64–2.81 (m, 3 H), 3.62 (dd, J = 14.5, 5.0 Hz,
1 H), 3.84 (d, J = 14 Hz, 1 H), 4.40 (d, J = 4.0 Hz, 1 H), 7.09–7.19
(m, 4 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.74 (d, J = 8.0 Hz, 2 H); δ (cis-
3d) = 0.87 (d, J = 6.5 Hz, 3 H), 1.12 (d, J = 7.0 Hz, 3 H), 1.16 (d,
J = 6.5 Hz, 3 H), 2.37 (s, 3 H), 2.56 (dd, J = 8.5, 3.5 Hz, 2 H), 3.10
(dd, J = 15.5, 10.5 Hz, 1 H), 4.14 (ddd, J = 13.5, 8.2, 2.0 Hz, 1 H),
6.98 (d, J = 8.0 Hz, 2 H), 7.04 (d, J = 3.0 Hz, 2 H), 7.57 (d, J = 8.5
Hz, 2 H); other signals overlapped with the major diastereomer.
13C NMR (75 MHz, CDCl3): δ (trans-3d) = 19.6, 20.3, 20.6, 21.4,
27.9, 28.4, 29.3, 32.6, 46.8, 62.5, 122.6, 126.34, 126.36, 127.2,
127.3, 129.3, 131.5, 131.9, 133.7136.6, 139.4, 142.7; δ (cis-3d) =
19.3, 20.5, 20.7, 21.1, 25.0, 27.7, 28.3, 32.4, 46.8, 62.5, 122.5,
125.5, 126.0, 126.8, 127.0, 129.0, 132.2, 133.0, 133.9, 136.4, 137.6,
142.9.
IR (film): 3062, 2972, 2928, 1337, 1160, 674, 576 cm–1.
1H NMR (500 MHz, CDCl3): δ (trans-3b) = 1.04 (d, J = 7.0 Hz, 3
H), 1.07 (d, J = 6.5 Hz, 3 H), 1.99 (ddd, J = 15.5, 6.0, 4.0 Hz, 1 H),
2.26–2.33 (m, 1 H), 2.41 (s, 3 H), 2.69 (ddd, J = 15.0, 6.0, 4.0 Hz,
1 H), 2.78 (dd, J = 15.0, 6.5 Hz, 1 H), 2.82–2.85 (m, 1 H), 3.29 (dd,
J = 13.0, 3.5 Hz, 1 H), 3.70 (d, J = 13.0 Hz, 1 H), 4.52 (q, J = 6.5
Hz, 1 H), 7.11–7.14 (m, 2 H), 7.18–7.20 (m, 2 H), 7.27 (s, 1 H), 7.29
(s, 1 H), 7.75 (t, J = 2.0 Hz, 1 H), 7.77 (t, J = 2.0 Hz, 1 H); δ (cis-
3b) = 0.98 (d, J = 6.5 Hz, 3 H), 1.46 (d, J = 6.5 Hz, 3 H), 2.13 (ddd,
J = 16.5, 6.0, 3.5 Hz, 1 H), 2.26 (s, 3 H), 2.54–2.63 (m, 1 H), 3.10
(dd, J = 14.0, 9.5 Hz, 1 H), 3.86 (dd, J = 14.0, 6.7, 1.5 Hz, 1 H),
4.24 (q, J = 6.5 Hz, 1 H), 6.81 (t, J = 7.5 Hz, 1 H), 7.07–7.09 (m, 3
H), 7.63–7.70 (m, 3 H), 7.82 (d, J = 8.0 Hz, 1 H); other signals over-
lapped with the major diastereomer.
13C NMR (75 MHz, CDCl3): δ (trans-3b) = 15.6, 18.5, 21.5, 27.0,
28.1, 28.9, 44.6, 53.4, 122.1, 126.4, 126.6, 127.1, 127.6, 129.5,
130.5, 133.3, 133.4, 136.1, 138.6, 142.9; δ (cis-3b) = 19.7, 20.9,
21.3, 26.7, 27.1, 29.7, 46.2, 53.0, 122.9, 125.8, 126.1, 126.9, 127.3,
129.3, 129.6, 131.3, 135.6, 135.9, 137.2, 143.1.
LRMS: m/z (%) = 367 (0.46) [M+●], 352 (4.5), 196 (14.1), 128
(14.5), 115 (12.5), 91 (100).
HRMS (ESI): m/z calcd for [C24H29NO2S + Na]+: 418.1817; found:
418.1815.
4-Cyclohexyl-1-methyl-3-tosyl-1,2,3,4,5,6-hexahydroben-
zo[f]isoquinoline (3e)
The reaction was performed by following the typical procedure, but
using 1 (0.11 g, 0.32 mmol), 2e (0.036 mL, 0.32 mmol), CH2Cl2
(1.3 mL), and I2 (0.0082 g, 0.032 mmol) to give a colorless viscous
oil; yield: 0.071 g (0.17 mmol, 54%; cis/trans = 1:6).
HRMS (ESI): m/z calcd for [C24H29NO2S + H]+: 368.1684; found:
368.1672.
IR (film): 3062, 2928, 2852, 1336, 1151, 672 cm–1.
1-Methyl-4-propyl-3-tosyl-1,2,3,4,5,6-hexahydrobenzo[f]iso-
quinoline (3c)
The reaction was performed by following the typical procedure, but
using 1 (0.11 g, 0.30 mmol), 2c (0.021 g, 0.30 mmol), CH2Cl2 (1.1
mL), and I2 (0.076 g, 0.030 mmol) to give a white solid: yield: 0.098
g (0.23 mmol, 76%; cis/trans = 1:6); mp 129.7–132.6 °C
1H NMR (300 MHz, CDCl3): δ (trans-3e) = 0.69 (d, J = 6.9 Hz, 3
H), 0.94–1.13 (m, 6 H), 1.66–1.69 (m, 4 H), 2.04 2.14 (m, 1 H),
2.28–2.41 (m, 2 H), 2.37 (s, 3 H), 2.66–2.79 (m, 3 H), 3.61 (dd,
J = 14.2, 4.8 Hz, 1 H), 3.82 (d, J = 14.1 Hz, 1 H), 4.37 (d, J = 3.6
Hz, 1 H), 7.04–7.18 (m, 4 H), 7.22 (s, 1 H), 7.25 (s, 1 H), 7.71 (t,
J = 2.4 Hz, 1 H), 7.75 (t, J = 2.1 Hz, 1 H).
IR (film): 3063, 2959, 2872, 1337, 1155, 674 cm–1.
13C NMR (75 MHz, CDCl3): δ (trans-3e) = 19.7, 21.4, 26.2, 26.8,
27.2, 27.9, 28.4, 29.6, 30.6, 31.5, 42.9, 47.0, 62.4, 122.6, 126.4,
127.2, 127.3, 129.3, 131.4, 131.7, 133.8, 136.6, 139.4, 142.7.
1H NMR (500 MHz, CDCl3): δ (trans-3c) = 0.71 (t, J = 7.0 Hz, 3 H),
0.89 (d, J = 7.0 Hz, 3 H), 1.08–1.17 (m, 1 H), 1.18–1.28 (m, 1 H),
1.46–1.54 (m, 1 H), 1.59–1.71 (m, 2 H), 2.04 (ddd, J = 15.4, 6.0, 3.0
Hz, 1 H), 2.26–2.33 (m, 1 H), 2.39 (s, 3 H), 2.69 (ddd, J = 15.1, 6.0,
Synthesis 2013, 45, 1076–1082
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Synthesis and Antiproliferative Activity of Hexahydrobenzo[f]isoquinolines
1081
HRMS (ESI): m/z calcd for [C27H33NO2S + Na]+: 458.2130; found:
458.2139.
(dd, J = 14.5, 6.5 Hz, 1 H), 5.37 (s, 1 H), 7.34 (s, 1 H), 7.35 (s, 1 H),
7.61 (s, 1 H), 7.63 (s, 1 H), 7.66 (s, 1 H), 7.67 (s, 1 H), 8.21 (s, 1 H),
8.23 (s, 1 H); other signals overlapped with the major diastereomer.
13C NMR (75 MHz, CDCl3): δ (trans-3h) = 18.7, 21.3, 26.7, 28.0,
28.8, 45.9, 59.7, 122.5, 123.3, 126.7, 126.9, 127.4, 127.8, 129.1,
129.4, 129.8, 132.7, 133.3, 136.0, 137.4, 143.1, 145.1, 147.5; δ (cis-
3h) = 18.5, 21.3, 26.2, 27.2, 27.6, 46.5, 60.2, 123.0, 123.7, 126.0,
126.7, 127.4, 128.4, 129.2, 129.9, 130.2, 132.6, 134.9, 135.8, 136.8,
143.7, 146.5, 147.7.
1-Methyl-4-phenyl-3-tosyl-1,2,3,4,5,6-hexahydrobenzo[f]iso-
quinoline (3f)
The reaction was performed by following the typical procedure, but
using 1 (0.118 g, 0.34 mmol), 2f (0.037 mL, 0.34 mmol), CH2Cl2
(1.4 mL), and I2 (0.0088 g, 0.034 mmol) to give a colorless viscous
oil:32 yield: 0.095 g (0.22 mmol, 64%; cis/trans = 1:1.15).
4-(4-Methoxyphenyl)-1-methyl-3-tosyl-1,2,3,4,5,6-hexahydro-
benzo[f]isoquinoline (cis- and trans-3g)
HRMS (ESI): m/z calcd for [C27H27N2O4S + H]+: 475.1692; found:
475.1687.
The reaction was performed by following the typical procedure, but
using 1 (0.10 g, 0.30 mmol), 2g (0.041 mL, 0.30 mmol), CH2Cl2
(1.4 mL), and I2 (0.0076 g, 0.030 mmol) to give a yellow oil; yield:
0.078 g (0.17 mmol, 56%; cis/trans = 1:1). This was subjected to
further purification by flash column chromatography (5% EtOAc–
hexanes) to give pure samples of cis- and trans-3g.
1-Methyl-4-(4-nitrophenyl)-3-tosyl-1,2,3,4,5,6-hexahydroben-
zo[f]isoquinoline (3h); Solvent-Free Method
The reaction was performed by following the typical procedure, but
using 1 (0.072 g, 0.21 mmol), 3h (0.032 g, 0.21 mmol), and I2
(0.0055 g, 0.021 mmol), and omitting the CH2Cl2, to give a yellow
oil; yield: 0.042 g (0.088 mmol, 41%; cis/trans = 1:2).
cis-3g
IR (film): 3060, 2954, 2920, 2858, 1509, 1337, 1157, 637 cm–1.
1-Methyl-4-styryl-3-tosyl-1,2,3,4,5,6-hexahydrobenzo[f]iso-
quinoline (3i)
The reaction was performed by following the typical procedure, but
using 1 (0.10 g, 0.29 mmol), 2i (0.039 mL, 0.29 mmol), CH2Cl2 (1.2
mL), and I2 (0.0075 g, 0.029 mmol) to give a yellow oil; yield: 0.10
g (0.22 mmol, 75%, cis/trans = 1:2.4).
1H NMR (300 MHz, CDCl3): δ = 0.94 (d, J = 6.6 Hz, 3 H), 1.90–
2.03 (m, 2 H), 2.19 (s, 3 H), 2.52–2.72 (m, 3 H), 2.83 (dd, J = 14.5,
10.5 Hz, 1 H), 3.79–3.82 (m, 1 H), 3.84 (s, 3 H), 5.32 (s, 1 H), 6.69–
6.73 (m, 1 H), 6.86 (m, 2 H), 7.03 (s, 1 H), 7.06 (s, 1 H), 7.07–7.10
(m, 3 H), 7.36–7.41 (m, 2 H), 7.60 (t, J = 1.8 Hz, 1 H), 7.63 (t,
J = 1.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ =18.4, 21.2, 26.1, 27.2, 27.8, 45.8,
55.3, 60.2, 113.8, 122.9, 125.7, 126.3, 126.9, 127.2, 129.2, 130.2,
130.9, 132.0, 133.2, 133.7, 136.1, 137.6, 143.1, 159.4.
IR (film): 3060, 3026, 2928, 2872, 1598, 1339, 1155, 753, 674, 584
cm–1.
1H NMR (500 MHz, CDCl3): δ (trans-3i) = 1.27 (d, J = 7.0 Hz, 3
H), 2.02–2.09 (m, 1 H), 2.11–2.21 (m, 1 H), 2.24 (s, 3 H), 2.62–2.71
(m, 2 H), 2.80 (dd, J = 15.0, 6.5 Hz, 1 H), 2.93–2.95 (m, 1 H), 3.23
(dd, J = 12.5, 3.5 Hz, 1 H), 3.80 (d, J = 12.0 Hz, 1 H), 4.96 (d,
J = 8.5 Hz, 1 H), 5.59 (dd, J = 15.5, 8.5 Hz, 1 H), 6.47 (d, J = 15.5
Hz, 1 H), 7.03–7.16 (m, 6 H), 7.18–7.32 (m, 5 H), 7.63 (t, J = 1.5
Hz, 1 H), 7.65 (s, 1 H); δ (cis-3i) = 1.00 (d, J = 6.5 Hz, 3 H), 2.23
(s, 3 H), 3.03 (dd, J = 14.0, 10.0 Hz, 1 H), 3.93 (dd, J = 13.5. 6.5,
1.5 Hz, 1 H), 4.83 (d, J = 7.0 Hz, 1 H), 6.12 (dd, J = 15.5, 6.5 Hz, 1
H), 6.56 (d, J = 16.0 Hz, 1 H), 6.88 (dd, J = 7.5 Hz, 1 H), 7.66 (t,
J = 2.0 Hz, 1 H); other signals overlapped with the major diastereo-
mer.
HRMS (ESI): m/z calcd for [C28H29NO3S + Na]+: 482.1766; found:
482.1747.
trans-3g
IR (film): 3060, 2962, 2927, 2872, 1510, 1335, 1154, 636 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.25 (d, J = 6.6 Hz, 3 H), 1.87–
1.93 (m, 2 H), 2.30 (s, 3 H), 2.58–2.79 (m, 2 H), 2.98–3.05 (m, 1 H),
3.37 (dd, J = 12.9, 3.6 Hz, 1 H), 3.68 (dd, J = 12.6, 0.9 Hz, 1 H),
3.75 (s, 3 H), 5.45 (s, 1 H), 6.64–6.67 (m, 2 H), 6.98 (s, 1 H), 7.01
(s, 1 H), 7.08–7.17 (m, 4 H), 7.23–7.27 (m, 3 H), 7.32–7.36 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ (trans-3i) = 18.6, 21.3, 26.7, 28.2,
29.1, 45.9, 59.8, 122.3, 123.3, 126.4, 126.9, 127.2, 127.5, 127.7,
127.8, 128.3, 129.2, 129.7, 132.1, 133.3, 134.0, 136.1, 136.2, 137.8,
142.7; δ (cis-3i) = 18.4, 26.6, 27.5, 27.9, 46.5, 59.1, 123.1, 125.9,
126.1, 126.6, 127.3, 127.7, 128.0, 128.5, 129.3, 131.8, 133.4, 133.8,
137.4, 143.1; other signals overlapped with the major diastereomer.
13C NMR (75 MHz, CDCl3): δ = 19.0, 21.6, 27.2, 28.4, 29.1, 45.9,
55.5, 60.4, 113.8, 122.6, 126.7, 127.10, 127.14, 127.9, 129.1, 130.3,
130.5, 130.6, 130.9, 132.1, 133.5, 136.5, 142.4, 159.7.
HRMS (ESI): m/z calcd for [C28H29NO3S + Na]+: 482.1766; found:
482.1764.
HRMS (ESI): m/z calcd for [C29H30NO2S + H]+: 456.1997; found:
456.1998.
4-(4-Methoxyphenyl)-1-methyl-3-tosyl-1,2,3,4,5,6-hexahydro-
benzo[f]isoquinoline (3g); Solvent-Free Method.
The reaction was performed by following the typical procedure, but
using 1 (0.083 g, 0.25 mmol), 2g (0.030 mL, 0.25 mmol), and I2
(0.0063 g, 0.025 mmol) and omitting the CH2Cl2, to give a yellow
oil; yield: 0.062 g (0.14 mmol, 55%, cis/trans = 1:1).
Antiproliferative Assay
Human tumor cell lines [U251 (glioma), MCF-7 (breast), NCI-
ADR/RES (ovarian expressing the multiple-drugs-resistance phe-
notype), 786–0 (renal), NCI-H460 (lung, non-small cells), PC-3
(prostate), OVCAR-03 (ovarian), HT-29 (colon) and K562 (leuke-
mia)] were kindly provided by the Frederick Cancer Research &
Development Center (National Cancer Institute, Frederick, MA,
USA). The HaCat cell line (immortalized human keratinocytes) was
kindly donated by Dr Ricardo Della Coletta, FOP/Unicamp, SP,
Brazil. Stock cultures were grown in RPMI 1640 medium (5 mL)
(Gibco BRL/Life Technologies) supplemented with 5% of fetal bo-
vine serum. Penicillin and streptomycin (1000 μg·mL–1:1000
UI·mL–1; 1 mL·L–1) were added to the experimental cultures. Cells
plated in 96-well plates (100 μL cells/well) were exposed to various
concentrations of compounds 3a–h diluted in DMSO (0.25, 2.5, 25,
or 250 μg·mL–1) at 37 °C under an atmosphere of 5% CO2 for 48 h.
The final concentration of DMSO did not affect the viability of the
cells. Afterwards, the cells were fixed with 50% trichloroacetic acid
and cell proliferation was determined by spectrophotometric quan-
tification (540 nm) of cellular protein content be means of the sul-
1-Methyl-4-(4-nitrophenyl)-3-tosyl-1,2,3,4,5,6-hexahydroben-
zo[f]isoquinoline (3h)
The reaction was performed by following the typical procedure, but
using 1 (0.080 g, 0.23 mmol), 2h (0.035 mL, 0.23 mmol), CH2Cl2
(1.1 mL), and I2 (0.0060 g, 0.023 mmol) to give a yellow oil; yield:
0.031 g (0.065 mmol, 28%; cis/trans = 1:2).
IR (film): 3059, 2966, 2927, 2852, 1521, 1347, 1156, 581 cm–1.
1H NMR (500 MHz, CDCl3): δ (trans-3h) = 1.23 (d, J = 7.0 Hz, 3
H), 1.79–1.94 (m, 2 H), 2.29 (s, 3 H), 2.59–2.70 (m, 1 H), 2.75–2.81
(m, 1 H), 3.08–3.10 (m, 1 H), 3.42 (d, J = 12.5, 3.5 Hz, 1 H), 3.79
(d, J = 13.0 Hz, 1 H), 5.56 (s, 1 H), 7.01 (s, 1 H), 7.02 (s, 1 H), 7.08–
7.18 (m, 4 H), 7.30 (t, J = 2.0 Hz, 1 H), 7.31 (t, J = 2.0 Hz, 1 H),
7.40 (t, J = 2.0 Hz, 1 H), 7.42 (t, J = 2.0 Hz, 1 H), 7.97 (t, J = 2.0
Hz, 1 H), 7.99 (t, J = 2.0 Hz, 1 H); δ (cis-3h) = 1.00 (d, J = 7.0 Hz,
3 H), 2.01–2.09 (m, 2 H), 2.22 (s, 3 H), 3.08–3.10 (m, 1 H), 3.84
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1076–1082

1082
C. A. Figueiredo et al.
PAPER
forhodamine B assay.35 Doxorubicin (0.025–25 μg·mL–1) was used
as a positive control. Three measurements were obtained at the be-
ginning of incubation (time zero, T0) and at 48 h post-incubation for
compound-free (C) and tested (T) cells. Cell proliferation was de-
termined according to the equation 100 × [(T – T0)/C – T0] for T0 <
T ≤ C or 100 × [(T – T0)/T0] for T ≤ T0. A concentration–response
curve was plotted for each cell line and from these curves, the value
of GI50 (the concentration producing a 50% inhibition in growth)
was determined by means of nonlinear regression analysis using
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Excel spreadsheet (Microsoft Corp.). Compounds were classified as
inactive (mean > 1.5), weakly active (1.1 < mean < 1.5), moderately
active (0 < mean < 1.1) or potently active (mean < 0) on the basis of
the NCI criteria for the mean of log GI50.34
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Acknowledgment
This work was financially supported by CAPES, FAPESP, and
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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Synthesis 2013, 45, 1076–1082
© Georg Thieme Verlag Stuttgart · New York