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Synthesis 2013; 45(8): 1076-1082
DOI: 10.1055/s-0032-1318478
paper
© Georg Thieme Verlag Stuttgart · New York

Iodine-Catalyzed Aza-Prins Cyclization: Metal-Free Synthesis and Antiproliferative Activity of Hexahydrobenzo[f]isoquinolines

Carlos A. M. Figueiredo
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   Email: luizfsjr@iq.usp.br
,
K. R. Kishore K. Reddy
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   Email: luizfsjr@iq.usp.br
,
Paula A. Monteiro
b   Divisão de Farmacologia e Toxicologia, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas (CPQBA), UNICAMP, CP6171, 13083-970 Campinas, SP, Brazil
,
João E. de Carvalho
b   Divisão de Farmacologia e Toxicologia, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas (CPQBA), UNICAMP, CP6171, 13083-970 Campinas, SP, Brazil
,
Ana L. T. G. Ruiz
b   Divisão de Farmacologia e Toxicologia, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas (CPQBA), UNICAMP, CP6171, 13083-970 Campinas, SP, Brazil
,
Luiz F. Silva Jr*
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   Email: luizfsjr@iq.usp.br
› Author Affiliations
Further Information

Publication History

Received: 30 January 2013

Accepted after revision: 25 February 2013

Publication Date:
13 March 2013 (online)

 
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Abstract

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.


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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 presence of an acid (Lewis or Brønsted). This reaction provides a powerful method for the synthesis of N-heterocycles.[1] [2] Thus, preparations of piperidines and tetrahydropyridines 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]isoquinolines through an iodine-catalyzed aza-Prins cyclization. On the basis of the potential biological activity of the target compounds[24] [25] [26] and our continuing efforts to discover new antitumor entities,[27] [28] we also examined the antiproliferative activities of the hexahydrobenzo[f]isoquinolines that we prepared.

N-[2-(3,4-Dihydronaphthalen-1-yl)propyl]-4-methylbenzenesulfonamide (1) was prepared from 1-tetralone in four steps: Reformatsky/dehydration reaction, reduction, Mitsunobu reaction, and hydrolysis of a tert-butoxycarbonyl group.[29] [30] [31] A series of commercially available aldehydes were used as the carbonyl components. On the basis of our previous works on Prins cyclization,[ 32,33 ] we performed the cyclizations by using 10 mol% of iodine as the catalyst in dichloromethane (Table [1]). When an unhindered aliphatic aldehyde such as formaldehyde, acetaldehyde, 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 were lower, although still within the practical range (entries 4 and 5). We also performed the reaction with aromatic aldehydes, including aldehydes substituted with electron-withdrawing and or electron-donating groups, and the reaction times in these cases were as much as three 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).

The reaction time for some of the reactions shown in Table [1] was relatively long (>24 hours). With solvent-free conditions and higher temperatures, it was possible to isolate the desired N-heterocyclic compounds in shorter reaction 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 assigned 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 catalyzed 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 species 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 alcohols with the same aldehydes, which give the cis-diastereomers preferentially.[ 32 ]

On the basis of the expected biological activity of hexahydrobenzo[f]isoquinolines 3, we evaluated their antiproliferative 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 doxorubicin (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 relevant results are listed in Table [3]. To analyze the GI50 parameter, we calculated the value of log GI50 from the GI50 value for each test compound against each tumor cell line tested (apart from the normal cell line HaCat), and then we took the average of these values. According to National Cancer Institute (NCI/EUA), if the value of the mean log GI50 is less than 1.50, the tested compound can be considered to be active and can be classified as showing weak (1.1 < mean log GI50 < 1.5), moderate (0 < mean log GI50 < 1.1) or potent (mean log GI50 < 0) activity.[ 34 ] On the basis of this criterion, compounds 3h, cis -3g and trans -3g were considered to be inactive (mean log GI50 > 1.5) (Table [3]), whereas compound 3f showed a weak antiproliferative effect (mean log GI50 = 1.4), and compounds 3c (mean log GI50 = 1.0) and 3d (mean log GI50 < 1.0) showed moderate activity. These results suggest that a lateral carbon chain is important to the antiproliferative effect. Alkyl groups, such as propyl (3c) or isopropyl (3d) are better substituents than aryl groups. When the aryl group was substituted by an electron-withdrawing group (3h) or electron-donating group (3g), the compounds were inactive. The compounds 3c and 3d showed similar moderate activities; however, 3c was more active toward K562 and NCI-ADR/RES, whereas 3d was more active toward PC-3, OVCAR-3, and MCF-7. Compound trans -3g selectively inhibited the growth of NCI-ADR/RES, OVCAR-3, PC-3, and K562, whereas cis -3g was active against PC-3 and NCI-ADR/RES.

Table 1 Iodine-Catalyzed Aza-Prins Cyclization in Dichloromethane

Entry

Aldehyde

Time (h)

Product

Yielda (%)

1

HCHO (2a)

 1.5

3a

63%

2

MeCHO (2b)

 3

3b

75% (cis/trans 1:5)

3

PrCHO (2c)

 3

3c

76% (cis/trans 1:6)

4

i-PrCHO (2d)

24

3d

50% (cis/trans 1:11)

5

CyCHO (2e)

48

3e

54% (cis/trans 1:6)

6

PhCHO (2f)

 5

3f

64% (cis/trans 1:1.15)

7

4-MeOC6H4CHO (2g)

72

3g

56% (cis/trans 1:1)

8

4-O2NC6H4CHO (2h)

72

3h

28% (cis/trans 1:2)

9

(E)-PhCH=CHCHO (2i)

24

3i

75% (cis/trans 1:2.4)

a Isolated yield.

Table 2 Iodine-Catalyzed Aza-Prins Cyclization under Solvent-Free Conditions

Entry

Aldehyde

Time (h)

Product

Yielda (%)

1

4-MeOC6H4CHO (2g)

6

3g

55% (cis/trans 1:1)

2

4-O2NC6H4CHO (2h)

4

3h

41% (cis/trans 1:2)

a Isolated yield.

In conclusion, we accomplished a metal-free synthesis of a series of hexahydrobenzo[f]isoquinolines 3 by means of an iodine-catalyzed aza-Prins cyclization of a homoallylic amine 1 with an aliphatic or aromatic aldehyde 2. The reaction can also be performed under solvent-free conditions. This protocol can be used to obtain other nitrogen heterocycles in an efficient manner. During this study, we also discovered new compounds that showed moderate antitumor activity and good selectivity toward various tumor cell lines

Table 3 Antiproliferative Activities (GI50; μg·mL–1) of Hexahydrobenzo[f]isoquinolines 3

Cell linea

Controlb

3c
(cis/trans 1:6)

3d
(cis/trans 1:10)

3f
(cis/trans 1:1.7)

3h
(cis/trans 1:2)

cis-3g

trans-3g
(cis/trans 1:6.2)

U251

  0.025

121.1

148.6

  45.3

>250

>250

>250

MCF-7

 <0.25

11.5

  5.8

  38.7

>250

  29.9

  83.2

NCI-ADR/RES

  0.19

 6.7

 10.1

   6.0

  19.6

  10.6

   2.7

OVCAR-3

  0.031

 4.1

  0.58

  15.8

>250

  61.3

   9.4

786-0

  0.025

93.1

 45.3

>250

>250

>250

  56.3

NCI-H460

 <0.25

53.4

 63.3

 100.8

>250

>250

>250

PC-3

 <0.25

 0.25

 <0.25

  <0.25

  <0.25

   1.8

   9.4

K562

  0.37

 0.80

  9.2

  20.1

   0.38

 231.2

  15.7

HT-29

  0.12

95.6

 86.4

 114.4

>250

  38.2

>250

HaCat

  0.068

50.2

 63.4

 133.0

>250

>250

>250

Mean log GI50 c

<–0.9 (P)

 1.0 (M)

 <1.0 (M)

   1.4 (W)

  >1.6 (I)

  >1.7 (I)

  >1.6 (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 ]

Zoom Image
Scheme 1 Mechanism for the iodine-catalyzed aza-Prins cyclization

All commercially available reagents were used without further purification 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/benzophenone. 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- anisaldehyde 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 solvent 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.


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N-[2-(3,4-Dihydronaphthalen-1-yl)propyl]-4-methylbenzenesulfonamide (1)

PPh3 (1.11 g, 4.23 mmol) and 2-(3,4-dihydronaphthalen-1-yl)propan-1-ol[ 29 ] (0.795 g, 4.23 mmol) were added to a stirred soln of TsNHBoc[30] [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 added. 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 purified by flash chromatography (30% EtOAc–hexanes) to give the intermediate tert-butoxycarbonyl derivative; yield: 1.36 g (3.06 mmol, 72%).

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 reduced pressure, and the residue was purified by flash chromatography (20% EtOAc–hexanes) to give 1 as a highly viscous oil; yield: 0.722 g (2.11 mmol, 50%).

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.


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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 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 extracted 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%).

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.

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).

HRMS (ESI): m/z calcd for [C21H23NO2S + Na]+: 376.1347; found: 376.1348.


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1,4-Dimethyl-3-tosyl-1,2,3,4,5,6-hexahydrobenzo[f]isoquinoline (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): 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 overlapped 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 + H]+: 368.1684; found: 368.1672.


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1-Methyl-4-propyl-3-tosyl-1,2,3,4,5,6-hexahydrobenzo[f]isoquinoline (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

IR (film): 3063, 2959, 2872, 1337, 1155, 674 cm–1.

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, 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.

HRMS (ESI): m/z calcd for [C24H29NO2S + H]+: 396.1997; found: 396.1995.


#

4-Isopropyl-1-methyl-3-tosyl-1,2,3,4,5,6-hexahydrobenzo[f]isoquinoline (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).

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.

HRMS (ESI): m/z calcd for [C24H29NO2S + Na]+: 418.1817; found: 418.1815.


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4-Cyclohexyl-1-methyl-3-tosyl-1,2,3,4,5,6-hexahydrobenzo[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).

IR (film): 3062, 2928, 2852, 1336, 1151, 672 cm–1.

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).

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.

HRMS (ESI): m/z calcd for [C27H33NO2S + Na]+: 458.2130; found: 458.2139.


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1-Methyl-4-phenyl-3-tosyl-1,2,3,4,5,6-hexahydrobenzo[f]isoquinoline (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).


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4-(4-Methoxyphenyl)-1-methyl-3-tosyl-1,2,3,4,5,6-hexahydrobenzo[f]isoquinoline (cis- and trans-3g)

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.


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cis-3g

IR (film): 3060, 2954, 2920, 2858, 1509, 1337, 1157, 637 cm–1.

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.

HRMS (ESI): m/z calcd for [C28H29NO3S + Na]+: 482.1766; found: 482.1747.


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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 = 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.


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4-(4-Methoxyphenyl)-1-methyl-3-tosyl-1,2,3,4,5,6-hexahydrobenzo[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).


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1-Methyl-4-(4-nitrophenyl)-3-tosyl-1,2,3,4,5,6-hexahydrobenzo[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 (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.

HRMS (ESI): m/z calcd for [C27H27N2O4S + H]+: 475.1692; found: 475.1687.


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1-Methyl-4-(4-nitrophenyl)-3-tosyl-1,2,3,4,5,6-hexahydrobenzo[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).


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1-Methyl-4-styryl-3-tosyl-1,2,3,4,5,6-hexahydrobenzo[f]isoquinoline (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).

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 diastereomer.

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.

HRMS (ESI): m/z calcd for [C29H30NO2S + H]+: 456.1997; found: 456.1998.


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Antiproliferative Assay

Human tumor cell lines [U251 (glioma), MCF-7 (breast), NCI-ADR/RES (ovarian expressing the multiple-drugs-resistance phenotype), 786–0 (renal), NCI-H460 (lung, non-small cells), PC-3 (prostate), OVCAR-03 (ovarian), HT-29 (colon) and K562 (leukemia)] 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 bovine 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 quantification (540 nm) of cellular protein content be means of the sulforhodamine B assay.[ 35 ] Doxorubicin (0.025–25 μg·mL–1) was used as a positive control. Three measurements were obtained at the beginning of incubation (time zero, T0) and at 48 h post-incubation for compound-free (C) and tested (T) cells. Cell proliferation was determined 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 Origin­ 8.0 (OriginLab Corp.).[35] [36] The average activity (mean of log GI50) of each compound tested was also determined by using an 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 CNPQ­. We thank Dr. S.A.P. Quintiliano for initial experiments.

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synthesis.
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Scheme 1 Mechanism for the iodine-catalyzed aza-Prins cyclization