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Synlett 2014; 25(18): 2574-2578
DOI: 10.1055/s-0034-1379109
letter
© Georg Thieme Verlag Stuttgart · New York

New Synthetic Approach for the Preparation of 1-Aryl-3,4-dihydro­isoquinolines by Liebeskind–Srogl Reaction

Péter Ábrányi-Balogh*
a   Egis Pharmaceuticals Plc., Chemical Research Division, P.O. Box 100, 1475 Budapest, Hungary
b   Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, P.O. Box 91, 1521 Budapest, Hungary   Email: abpeter@gmail.com
,
Péter Slégel
a   Egis Pharmaceuticals Plc., Chemical Research Division, P.O. Box 100, 1475 Budapest, Hungary
,
Balázs Volk
a   Egis Pharmaceuticals Plc., Chemical Research Division, P.O. Box 100, 1475 Budapest, Hungary
,
László Pongó
a   Egis Pharmaceuticals Plc., Chemical Research Division, P.O. Box 100, 1475 Budapest, Hungary
,
Mátyás Milen
a   Egis Pharmaceuticals Plc., Chemical Research Division, P.O. Box 100, 1475 Budapest, Hungary
b   Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, P.O. Box 91, 1521 Budapest, Hungary   Email: abpeter@gmail.com
› Author Affiliations
Further Information

Publication History

Received: 03 July 2014

Accepted after revision: 18 August 2014

Publication Date:
07 October 2014 (online)

 
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Dedicated to Professor József Reiter on the occasion of his 75th birthday

Abstract

An efficient synthetic methodology has been developed to construct 1-aryl-3,4-dihydroisoquinoline derivatives. The reaction was performed under neutral conditions by a palladium-catalyzed desulfitative carbon–carbon cross-coupling protocol.


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Key words

isoquinolines - cross-coupling - Liebeskind–Srogl reaction - arylation - CuTC

The isoquinolines constitute an important class of both simple and complex alkaloids.[1] They also have been used as intermediates in organic synthesis. For example, some isoquinoline derivatives are utilized as chiral ligands for catalytic asymmetric transformations[2] and as electrophosphorescent iridium complexes.[3] Moreover, isoquinolines and their saturated counterparts such as dihydroisoquinolines and tetrahydroisoquinolines possess a vast spectrum of biological and pharmaceutical activities including antibacterial,[4] antitumor,[5] antitubercular,[6] antiplasmodial,[7] anti-HIV,[8] and antifungal effects[9] and some representatives are noncompetitive AMPA receptor antagonists.[10] An important member of the tetrahydroisoquinoline family is solifenacin (Vesicare®), A competitive cholinergic receptor antagonist which is developed for treating contraction of overactive bladder.[11] Other compounds containing 1-aryl-3,4-dihydroisoquinoline units represent a potent series of c-Jun N-terminal kinase 3 (JNK3) inhibitors (Figure [1]).[12]

1-Substituted-3,4-dihydroisoquinolines were also tested in vitro against the leukemia L 1210 cell line.[13] Furthermore, certain 1-aryl-3,4-dihydroisoquinolines have been used as starting materials of several alkaloid derivatives and chiral tetrahydroisoquinolines.[14]

In continuation of our efforts to synthesize new alkaloid derivatives,[15] we now describe a simple procedure for the preparation of 1-aryl-3,4-dihydroisoquinolines. In general, 3,4-dihydroisoquinolines have been constructed by Bischler–Napieralski cyclization. This ring-closure reaction traditionally requires harsh conditions, for example, treatment of the amide formed from phenylethylamine with POCl3, P2O5, or polyphosphoric acid (PPA) at high temperature and long reaction time.[16]

Zoom Image
Figure 1 Structure of some important isoquinoline derivatives

In the present paper, a different approach was used. 1-Aryl-3,4-dihydroisoquinoine target compounds have now been prepared by the application of the Liebeskind–Srogl protocol,[17] a palladium-catalyzed cross-coupling reaction. The starting material of the cross coupling, 1-(methylsulfanyl)-3,4-dihydroisoquinoline (1) was prepared according to our earlier procedure based on a microwave-assisted thionation reaction from commercially available 1,2,3,4-tetrahydroisoquinoline, followed by an S-alkylation step with methyl iodide.[18]

Zoom Image
Scheme 1 Arylation of 1-(methylsulfanyl)-3,4-dihydroisoquinoline (1)

At the beginning of our investigations, the conditions of the coupling reaction (Scheme [1]) were chosen based on the similar and optimized reactions of analogous nitrogen heterocycles described by Kappe and Prokopcová.[19] 3 Equiv. of copper(I)-thiophene-2-carboxylate (CuTC) as Cu(I) cofactor and 8 mol% of Pd(PPh3)4 in refluxing tetrahydrofuran (45–60 min) was in most cases suitable for the full conversion and good yields were observed (65–89%, Table [1], entries 1–3,5,8–14). It is worth mentioning that the 3-nitrophenyl derivative (3q) was obtained after a short reaction time (15 min) in a yield of 89% (Table [1], entry 17). However, for several analogues (Table [1], entries 4, 6, 7, 15, 16, 18, 19) increasing the reaction time to 3–7 h was indispensable for the full conversion and provided yields between 61 and 89%. This protocol[20] was used successfully in the presence of various functional groups, such as formyl (3d), methoxycarbonyl (3e), carboxybenzyl (3g), benzyloxy (3k), methylsulfanyl (3m), and tert-butoxycarbonyl (3p).

As the one exception, when using 4-(dimethylamino)phenylboronic acid (2f) as the starting material, the product 3f was isolated only in 32% yield (Table [1], entry 6). An inhibiting steric effect was observed by the ortho-substituted boronic acids that necessitated of longer reaction times (Table [1], entries 18 and 19). Moreover, there was no reaction detected in the case of 2-cyanophenyl- and 2-chlorophenylboronic acid. The increase of the amount of the boronic acid to two equivalents also did not result in any success, nor did the increase in reaction temperature by refluxing in 1,4-dioxane.

Table 1 Reaction Details for the Arylation of 1-(Methylsulfanyl)-3,4-Dihydroisoquinoline (1)a

Entry

3

Ar

Time (h)

Yield (%)b

 1

3a

Ph

0.75

78

 2

3b

4-MeC6H4

1

83

 3

3c

4-F3CC6H4

0.75

76

 4

3d

4-OHCC6H4

3

89

 5

3e

4-MeO2CC6H4

1

85

 6

3f

4-Me2NC6H4

4

32

 7

3g

4-CbzHNC6H4

4

88

 8

3h

4-MeOC6H4

1

82

 9

3i

3,4-(MeO)2C6H3

1

88

10

3j

1,3-benzodioxol-5-yl

1

71

11

3k

4-BnOC6H4

1

82

12

3l

4-FC6H4

0.75

89

13

3m

4-MeSC6H4

1

65

14

3n

4-ClC6H4

1

85

15

3o

3-NCC6H4

3

65

16

3p

3-BocHNC6H4

4

76

17

3q

3-O2NC6H4

0.25

89

18

3r

2-MeOC6H4

3

71

19

3s

2-FC6H4

7

61

a Reaction conditions: CuTC (3 equiv), Pd(PPh3)4 (8 mol%), boronic acid (1.2 equiv), reflux, THF.

b Yields are given for isolated products.

The application of phenylboronic acid pinacol ester instead of phenylboronic acid (2a) proved to be disadvantageous resulting in only traces of the desired 1-phenyl-3,4-dihydroisoquinoline (3a) as, under the same conditions, detected by HPLC–MS.

In the reaction of 1,4-benzenediboronic acid (2t) under the same conditions, two products were isolated: the appropriate bisisoquinoline derivative 3t and 1-phenyl-3,4-dihydroisoquinoline (3a) in yields of 23% and 30%, respectively (Scheme [2]). The unexpected compound 3a may be formed by deboronation in the transmetalation step of the cross-coupling circle.[17b]

Zoom Image
Scheme 2 The reaction of 1-(methylsulfanyl)-3,4-dihydroisoquinoline (1) with 1,4-benzenediboronic acid (2t)

As a continuation of our investigations, the precursor of 1, the isoquinoline embedded with a thioamide fragment 4, was examined for the Liebeskind–Srogl reaction with three boronic acids (2a,q,s, Scheme [3, ]Table [2]). It was found that applying the same conditions as in the reactions of 1, much lower yields were obtained. Even the most reactive 3-nitrophenylboronic acid (2q) could not approach the observed yield of the previous reaction with 1 (Table [2], entry 2) after a doubled reaction time.

Zoom Image
Scheme 3 The arylation of 3,4-dihydroisoquinoline-1(2H)-thione (4)

Table 2 Reaction Details for the Arylation of 3,4-Dihydroisoquinoline-1(2H)-thione (4)a

Entry

3

Ar

Time (h)

Yield (%)b

1

3a

Ph

0.75

66

2

3q

3-O2NC6H4

0.5

56

3

3s

2-FC6H4

7

36

a Reaction conditions: CuTC (3 equiv), Pd(PPh3)4 (8 mol%), boronic acid (1.2 equiv), reflux, THF.

b Yields are given for isolated products.

All the dihydroisoquinoline derivatives 3a–t prepared were characterized by IR, 1H NMR, and 13C NMR spectroscopy and mass spectrometry. Products 3a,b,h,i,k,m,n,q,r have been described and characterized previously, while compounds 3c–g,j,l,o,p,s,t have not been fully characterized or are new.

In conclusion, a simple and convenient method has been developed for the synthesis of 1-aryl-3,4-dihydroisoquinoline based on the Liebeskind–Srogl reaction. The advantages of this method can be enumerated as applying a mild and neutral process, coupling a variety of boronic acids, and also enabling to substitute isoquinolines with aryl groups that are sensitive to the harsh conditions of Bischler–Napieralski reaction. Most of the arylations were completed within one hour and preceded in high yields. It was found that the 1-(methylsulfanyl)-3,4-dihydroisoquinoline (1) is a more reactive species than the 3,4-dihydroisoquinoline-1(2H)-thione (4).


#

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/products/ejournals/journal/ 10.1055/s-00000083.
  • Supporting Information

  • References and Notes

  • 6 Kumar P, Dhawan KN, Kishore K, Bhargava KP. J. Heterocycl. Chem. 1982; 19: 677
    Search in Google Scholar
  • 7 Urverg-Ratsimamanga S, Rasoanaivo P, Rafatro H, Robijaona B, Rakato-Ratsimamanga A. Ann. Trop. Med. Parasitol. 1994; 88: 271
    Search in Google Scholar
  • 9 Liu LT, Lin Y.-C, Wang C.-LJ, Lin M.-S, Yen S.-C, Chen H.-J. Bioorg. Med. Chem. Lett. 1996; 6: 1335
    CrossrefSearch in Google Scholar
  • 10 Gitto R, Barecca ML, De Luca L, De Sarro G, Ferreri G, Quartarone S, Russo E, Constanti A, Chimirri A. J. Med. Chem. 2003; 46: 197
    CrossrefPubMedSearch in Google Scholar
  • 12 Christopher JA, Atkinson FL, Bax BD, Brown MJ. B, Champigny AC, Chuang TT, Jones EJ, Mosley JE, Musgrave JR. Bioorg. Med. Chem. Lett. 2009; 19: 2230
    CrossrefSearch in Google Scholar
  • 13 Bermejo A, Andreu I, Suvire F, Leonce S, Caignard DH, Renard P, Pierre A, Enriz RD, Cortes D, Cabedo N. J. Med. Chem. 2002; 45: 5058
    CrossrefSearch in Google Scholar
    • 16a Whaley WM, Govindachari TR. Organic Reactions . Roger Adams. John Wiley and Sons; New York: 1951. Vol. VI. 74-150
      Search in Google Scholar
    • 16b Horne DB, Tamayo NA, Bartberger MD, Bo Y, Clarine J, Davis DD, Gore VK, Kaller MR, Lehto SG, Ma VV, Nishimura N, Nguyen TT, Tang P, Wang W, Youngblood BD, Zhang M, Gavva NR, Monenschein H, Norman MH. J. Med. Chem. 2014; 57: 2989
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    • 16c Gray MM, Cheng BK, Mick SJ, Lair CM, Contreras PC. J. Med. Chem. 1989; 32: 1242
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  • 20 General Procedure for the Synthesis of 1-Aryl-3,4-dihydroisoquinolines To the stirred solution of 1-(methylsulfanyl)-3,4-dihydroisoquinoline (1, 1.0 mmol, 0.18 g) in THF (10 mL) under argon atmosphere arylboronic acid (1.2 mmol), CuTC (3 equiv, 3.0 mmol, 0.57 g), and Pd(PPh3)4 (8 mol%, 0.08 mmol, 92 mg) were added. The reaction was followed by TLC and HPLC–MS. The mixture was refluxed until the starting material disappeared. After cooling, the solvent was evaporated and CHCl3–MeOH (7:1) mixture (50 mL) was added. The crude reaction mixture was subsequently washed with 25% aq NH3 (2 × 25 mL). The aqueous layer was extracted with CHCl3–MeOH (7:1) mixture (2 × 25 mL). The combined organic phase was dried over Na2SO4 and the residue after evaporation purified by flash chromatography (silica gel 60 PF254) using CH2Cl2–MeOH as the eluents. 1-[4-(Trifluoromethyl)phenyl]-3,4-dihydroisoquinoline (3c) Yield 0.21 g (76%), white crystals, mp 77–78 °C. IR (KBr): 2958, 1610, 1565, 1323, 1109, 846 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.73–7.68 (m, 4 H), 7.41–7.39 (m, 1 H), 7.30–7.24 (m, 2 H), 7.19–7.18 (m, 1 H), 3.90–3.67 (m, 2 H), 2.82 (t, J = 7.4 Hz, 2 H) ppm; lit.:22 1H NMR (400 MHz, CDCl3): δ = 7.70 (m, 4 H), 7.40 (m, 1 H), 7.26 (m, 2 H), 7.20 (m, 1 H), 3.88 (m, 2 H), 2.82 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.2, 142.5, 138.7, 131.2 (q, J = 33.0 Hz), 131.0, 129.2, 128.3, 127.6, 127.5, 126.7, 125.1 (q, J = 3.8 Hz), 124.1 (q, J = 272.0 Hz), 47.9, 26.2 ppm. HRMS: m/z calcd for C16H13NF3 [M + H]+: 276.1000; found: 276.1002. 4-(3,4-Dihydroisoquinolin-1-yl)benzaldehyde (3d) Yield 0.21 g (89%), pale yellow crystals, mp 102–104 °C. IR (KBr): 2940, 1702, 1604, 1203 cm–1. 1H NMR (500 MHz, CDCl3): δ = 10.09 (s, 1 H), 7.96–7.94 (m, 2 H), 7.78–7.76 (m, 2 H), 7.41–7.40 (m, 1 H), 7.30–7.28 (m, 1 H), 7.27–7.25 (m, 1 H), 7.19–7.17 (m, 1 H), 3.90 (t, J = 7.3 Hz, 2 H), 2.83 (t, J = 7.3 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 191.8, 166.4, 144.8, 138.7, 136.8, 131.0, 129.5, 129.4, 128.3, 127.6, 127.4, 126.7, 47.9, 26.1 ppm. HRMS: m/z calcd for C16H14NO [M + H]+: 236.1075; found: 236.1081. Methyl 4-(3,4-Dihydroisoquinolin-1-yl)benzoate (3e) 21 Yield 0.23 g (85%), yellow oil. IR (film): 2950, 1724, 1610, 1279, 1104 cm–1. 1H NMR (500 MHz, CDCl3): δ = 8.11–8.09 (m, 2 H), 7.68–7.67 (m, 2 H), 7.42–7.38 (m, 1 H), 7.29–7.24 (m, 2 H), 7.19–7.18 (m, 1 H), 3.95 (s, 3 H), 3.90–3.87 (m, 2 H), 2.82 (t, J = 7.3 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.8, 166.6, 143.3, 138.7, 130.9, 130.8, 129.4, 128.8, 128.4, 127.6, 127.5, 126.7, 52.2, 47.8, 26.2 ppm. HRMS: m/z calcd for C17H16NO2 [M + H]+: 266.1181; found: 266.1171. 4-(3,4-Dihydroisoquinolin-1-yl)-N,N-dimethylaniline (3f) Yield 0.08 g (32%), yellow crystals, mp 102–105 °C (MeCN). IR (KBr): 3444, 2888, 1608, 1525, 1346, 1195, 823 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.55–7.53 (m, 2 H), 7.40–7.36 (m, 2 H), 7.26–7.25 (m, 1 H), 6.74–6.73 (m, 2 H), 3.78 (t, J = 7.1 Hz, 2 H), 3.00 (s, 3 H), 2.76 (t, J = 7.1 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.7, 151.3 139.3, 130.2, 130.0, 129.1, 128.2, 127.2, 126.7, 126.3, 111.5, 65.5, 40.4, 26.6 ppm. HRMS: m/z calcd for C17H19N2 [M + H]+: 251.1548; found: 251.1562. Benzyl [4-(3,4-Dihydroisoquinolin-1-yl)phenyl]-carbamate (3g) Yield 0.31 g (88%), white crystals, mp 194–195 °C (MeCN). IR (KBr): 3337, 2976, 1703, 1609, 1591, 1534, 1230, 1056, 744 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.57–7.55 (m, 2 H), 7.46–7.32 (m, 8 H), 7.31–7.21 (m, 3 H), 6.96 (s, 1 H), 5.22 (s, 2 H), 3.81 (t, J = 7.2 Hz, 2 H), 2.78 (t, J = 7.1 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.6, 153.2, 138.9, 135.9, 134.0, 130.6, 129.7, 128.7, 128.6, 128.4, 127.8, 127.4, 126.5, 118.0, 67.1, 47.5, 26.3 ppm. HRMS: m/z calcd for C23H21N2O2 [M + H]+: 357.1603; found: 357.1598. 1-(1,3-Benzodioxol-5-yl)-3,4-dihydroisoquinoline (3j) 22 Yield 0.18 g (71%), yellow oil. IR (film): 2940, 1600, 1486, 1440, 1232, 1039, 936, 746 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.38–7.36 (m, 1 H), 7.33–7.31 (m, 1 H), 7.28–7.24 (m, 2 H), 7.14–7.09 (m, 2 H), 6.86–6.84 (m, 1 H), 6.00 (s, 2 H), 3.82–3.78 (m, 2 H), 2.78 (t, J = 7.3 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.4, 148.6, 147.5, 139.0, 133.1, 130.6, 128.7, 127.9, 127.3, 126.5, 123.1, 109.3, 107.8, 101.2, 47.5, 26.3 ppm. HRMS: m/z calcd for C16H13NO2 [M+H]+: 251.0946; 251.0942. 1-(4-Fluorophenyl)-3,4-dihydroisoquinoline (3l) 23 Yield 0.20 g (89%), yellow crystals, mp 37–38 °C (hexane). IR (KBr): 2941, 1604, 1506, 1152, 847 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.61–7.58 (m, 2 H), 7.41–7.37 (m, 1 H), 7.28–7.24 (m, 3 H), 7.12–7.09 (m, 2 H), 3.83 (t, J = 7.1 Hz, 2 H), 2.80 (t, J = 7.2 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.2, 163.5 (d, J = 249.0 Hz), 138.9, 135.1, 130.8, 130.7 (d, J = 8.3 Hz), 128.6, 127.7, 127.5, 126.6, 115.1 (d, J = 22.0 Hz), 47.6, 26.3 ppm. HRMS: m/z calcd for C15H13NF [M + H]+: 226.1032; found: 226.1033. 3-(3,4-Dihydroisoquinolin-yl)benzonitrile (3o) Yield 0.15 g (65%), pale yellow oil. IR (film): 2943, 2230, 1611, 1568, 1310, 708 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.93–7.92 (m, 1 H), 7.87–7.85 (m, 1 H), 7.74–7.72 (m, 1 H), 7.56–7.53 (m, 1 H), 7.44–7.41 (m, 1 H), 7.31–7.26 (m, 2 H), 7.17–7.15 (m, 1 H), 3.87 (t, J = 7.2 Hz, 2 H), 2.82 (t, J = 7.3 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 165.4, 140.2, 138.7, 133.0, 132.7, 132.4, 131.2, 129.0, 127.9, 127.7, 127.2, 126.8, 118.4, 112.5, 47.8, 26.1 ppm. HRMS: m/z calcd for C16H13N2 [M + H]+: 233.1079; found: 233.1069. tert-Butyl [3-(3,4-Dihydroisoquinolin-1-yl)phenyl]-carbamate (3p) Yield 0.25 g (76%), yellow oil. IR (KBr): 3232, 2975, 1723, 1609, 1549, 1240, 1159, 777 cm–1. 1H NMR (500 MHz, DMSO-d 6): δ = 9.42 (s, 1 H), 7.74 (s, 1 H), 7.64–7.61 (m, 1 H), 7.56–7.53 (m, 1 H), 7.44 (t, J = 7.4 Hz, 1 H), 7.36–7.28 (m, 3 H), 7.16 (d, J = 7.5 Hz, 1 H), 7.10 (d, J = 7.5 Hz, 1 H), 3.71 (t, J = 7.2 Hz, 2 H), 2.73 (t, J = 7.2 Hz, 2 H) ppm. 13C NMR (125 MHz, DMSO-d 6): δ = 165.8, 152.9, 139.5, 139.3, 138.6, 130.8, 128.9, 128.4, 127.6, 127.3, 126.8, 122.4, 119.0, 118.3, 79.2, 47.1, 28.3, 25.8 ppm. HRMS: m/z calcd for C20H23N2O2 [M + H]+: 323.1760; found: 323.1743. 1-(2-Fluorophenyl)-3,4-dihydroisoquinoline (3s) 24 Yield 0.14 g (61%), yellow crystals, mp 79–80 °C (i-Pr2O). IR (KBr): 3444, 2946, 1612, 1447, 1210, 768 cm-1. 1H NMR (500 MHz, CDCl3): δ = 7.53–7.50 (m, 1 H), 7.44–7.36 (m, 2 H), 7.26–7.21 (m, 3 H), 7.13–7.07 (m, 2 H), 3.90 (br s, 2 H), 2.87 (br s, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 163.9, 161.1, 160.0, 159.1, 137.2, 130.9, 130.8, 130.7, 127.4, 127.0 (d, J = 15.1 Hz), 124.3 (d, J = 3.4 Hz), 115.8 (d, J = 22.0 Hz), 94.8, 47.8, 26.0 ppm. HRMS: m/z calcd for C15H13NF [M + H]+: 226.1032; found: 226.1031. 1,1′-Benzene-1,4-diyldi-3,4-dihydroisoquinoline (3t) Yield 0.04 g (23%), white crystals, mp 198–199 °C (MeCN). IR (KBr): 3421, 2942, 1603, 1315 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.66–7.62 (m, 4 H), 7.48–7.45 (m, 2 H), 7.39–7.38 (m, 2 H), 7.36–7.32 (m, 2 H), 7.25–7.24 (m, 2 H), 3.76 (br s, 4 H), 2.77 (br s, 4 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 165.5, 139.4, 138.7, 130.9, 128.5, 127.8, 127.2, 126.9, 47.3, 25.8 ppm. HRMS: m/z calcd for C24H21N2 [M + H]+: 337.1705; found: 337.1711.
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  • References and Notes

  • 6 Kumar P, Dhawan KN, Kishore K, Bhargava KP. J. Heterocycl. Chem. 1982; 19: 677
    Search in Google Scholar
  • 7 Urverg-Ratsimamanga S, Rasoanaivo P, Rafatro H, Robijaona B, Rakato-Ratsimamanga A. Ann. Trop. Med. Parasitol. 1994; 88: 271
    Search in Google Scholar
  • 9 Liu LT, Lin Y.-C, Wang C.-LJ, Lin M.-S, Yen S.-C, Chen H.-J. Bioorg. Med. Chem. Lett. 1996; 6: 1335
    CrossrefSearch in Google Scholar
  • 10 Gitto R, Barecca ML, De Luca L, De Sarro G, Ferreri G, Quartarone S, Russo E, Constanti A, Chimirri A. J. Med. Chem. 2003; 46: 197
    CrossrefPubMedSearch in Google Scholar
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    CrossrefSearch in Google Scholar
  • 13 Bermejo A, Andreu I, Suvire F, Leonce S, Caignard DH, Renard P, Pierre A, Enriz RD, Cortes D, Cabedo N. J. Med. Chem. 2002; 45: 5058
    CrossrefSearch in Google Scholar
    • 16a Whaley WM, Govindachari TR. Organic Reactions . Roger Adams. John Wiley and Sons; New York: 1951. Vol. VI. 74-150
      Search in Google Scholar
    • 16b Horne DB, Tamayo NA, Bartberger MD, Bo Y, Clarine J, Davis DD, Gore VK, Kaller MR, Lehto SG, Ma VV, Nishimura N, Nguyen TT, Tang P, Wang W, Youngblood BD, Zhang M, Gavva NR, Monenschein H, Norman MH. J. Med. Chem. 2014; 57: 2989
      CrossrefSearch in Google Scholar
    • 16c Gray MM, Cheng BK, Mick SJ, Lair CM, Contreras PC. J. Med. Chem. 1989; 32: 1242
      CrossrefPubMedSearch in Google Scholar
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  • 20 General Procedure for the Synthesis of 1-Aryl-3,4-dihydroisoquinolines To the stirred solution of 1-(methylsulfanyl)-3,4-dihydroisoquinoline (1, 1.0 mmol, 0.18 g) in THF (10 mL) under argon atmosphere arylboronic acid (1.2 mmol), CuTC (3 equiv, 3.0 mmol, 0.57 g), and Pd(PPh3)4 (8 mol%, 0.08 mmol, 92 mg) were added. The reaction was followed by TLC and HPLC–MS. The mixture was refluxed until the starting material disappeared. After cooling, the solvent was evaporated and CHCl3–MeOH (7:1) mixture (50 mL) was added. The crude reaction mixture was subsequently washed with 25% aq NH3 (2 × 25 mL). The aqueous layer was extracted with CHCl3–MeOH (7:1) mixture (2 × 25 mL). The combined organic phase was dried over Na2SO4 and the residue after evaporation purified by flash chromatography (silica gel 60 PF254) using CH2Cl2–MeOH as the eluents. 1-[4-(Trifluoromethyl)phenyl]-3,4-dihydroisoquinoline (3c) Yield 0.21 g (76%), white crystals, mp 77–78 °C. IR (KBr): 2958, 1610, 1565, 1323, 1109, 846 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.73–7.68 (m, 4 H), 7.41–7.39 (m, 1 H), 7.30–7.24 (m, 2 H), 7.19–7.18 (m, 1 H), 3.90–3.67 (m, 2 H), 2.82 (t, J = 7.4 Hz, 2 H) ppm; lit.:22 1H NMR (400 MHz, CDCl3): δ = 7.70 (m, 4 H), 7.40 (m, 1 H), 7.26 (m, 2 H), 7.20 (m, 1 H), 3.88 (m, 2 H), 2.82 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.2, 142.5, 138.7, 131.2 (q, J = 33.0 Hz), 131.0, 129.2, 128.3, 127.6, 127.5, 126.7, 125.1 (q, J = 3.8 Hz), 124.1 (q, J = 272.0 Hz), 47.9, 26.2 ppm. HRMS: m/z calcd for C16H13NF3 [M + H]+: 276.1000; found: 276.1002. 4-(3,4-Dihydroisoquinolin-1-yl)benzaldehyde (3d) Yield 0.21 g (89%), pale yellow crystals, mp 102–104 °C. IR (KBr): 2940, 1702, 1604, 1203 cm–1. 1H NMR (500 MHz, CDCl3): δ = 10.09 (s, 1 H), 7.96–7.94 (m, 2 H), 7.78–7.76 (m, 2 H), 7.41–7.40 (m, 1 H), 7.30–7.28 (m, 1 H), 7.27–7.25 (m, 1 H), 7.19–7.17 (m, 1 H), 3.90 (t, J = 7.3 Hz, 2 H), 2.83 (t, J = 7.3 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 191.8, 166.4, 144.8, 138.7, 136.8, 131.0, 129.5, 129.4, 128.3, 127.6, 127.4, 126.7, 47.9, 26.1 ppm. HRMS: m/z calcd for C16H14NO [M + H]+: 236.1075; found: 236.1081. Methyl 4-(3,4-Dihydroisoquinolin-1-yl)benzoate (3e) 21 Yield 0.23 g (85%), yellow oil. IR (film): 2950, 1724, 1610, 1279, 1104 cm–1. 1H NMR (500 MHz, CDCl3): δ = 8.11–8.09 (m, 2 H), 7.68–7.67 (m, 2 H), 7.42–7.38 (m, 1 H), 7.29–7.24 (m, 2 H), 7.19–7.18 (m, 1 H), 3.95 (s, 3 H), 3.90–3.87 (m, 2 H), 2.82 (t, J = 7.3 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.8, 166.6, 143.3, 138.7, 130.9, 130.8, 129.4, 128.8, 128.4, 127.6, 127.5, 126.7, 52.2, 47.8, 26.2 ppm. HRMS: m/z calcd for C17H16NO2 [M + H]+: 266.1181; found: 266.1171. 4-(3,4-Dihydroisoquinolin-1-yl)-N,N-dimethylaniline (3f) Yield 0.08 g (32%), yellow crystals, mp 102–105 °C (MeCN). IR (KBr): 3444, 2888, 1608, 1525, 1346, 1195, 823 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.55–7.53 (m, 2 H), 7.40–7.36 (m, 2 H), 7.26–7.25 (m, 1 H), 6.74–6.73 (m, 2 H), 3.78 (t, J = 7.1 Hz, 2 H), 3.00 (s, 3 H), 2.76 (t, J = 7.1 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.7, 151.3 139.3, 130.2, 130.0, 129.1, 128.2, 127.2, 126.7, 126.3, 111.5, 65.5, 40.4, 26.6 ppm. HRMS: m/z calcd for C17H19N2 [M + H]+: 251.1548; found: 251.1562. Benzyl [4-(3,4-Dihydroisoquinolin-1-yl)phenyl]-carbamate (3g) Yield 0.31 g (88%), white crystals, mp 194–195 °C (MeCN). IR (KBr): 3337, 2976, 1703, 1609, 1591, 1534, 1230, 1056, 744 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.57–7.55 (m, 2 H), 7.46–7.32 (m, 8 H), 7.31–7.21 (m, 3 H), 6.96 (s, 1 H), 5.22 (s, 2 H), 3.81 (t, J = 7.2 Hz, 2 H), 2.78 (t, J = 7.1 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.6, 153.2, 138.9, 135.9, 134.0, 130.6, 129.7, 128.7, 128.6, 128.4, 127.8, 127.4, 126.5, 118.0, 67.1, 47.5, 26.3 ppm. HRMS: m/z calcd for C23H21N2O2 [M + H]+: 357.1603; found: 357.1598. 1-(1,3-Benzodioxol-5-yl)-3,4-dihydroisoquinoline (3j) 22 Yield 0.18 g (71%), yellow oil. IR (film): 2940, 1600, 1486, 1440, 1232, 1039, 936, 746 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.38–7.36 (m, 1 H), 7.33–7.31 (m, 1 H), 7.28–7.24 (m, 2 H), 7.14–7.09 (m, 2 H), 6.86–6.84 (m, 1 H), 6.00 (s, 2 H), 3.82–3.78 (m, 2 H), 2.78 (t, J = 7.3 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.4, 148.6, 147.5, 139.0, 133.1, 130.6, 128.7, 127.9, 127.3, 126.5, 123.1, 109.3, 107.8, 101.2, 47.5, 26.3 ppm. HRMS: m/z calcd for C16H13NO2 [M+H]+: 251.0946; 251.0942. 1-(4-Fluorophenyl)-3,4-dihydroisoquinoline (3l) 23 Yield 0.20 g (89%), yellow crystals, mp 37–38 °C (hexane). IR (KBr): 2941, 1604, 1506, 1152, 847 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.61–7.58 (m, 2 H), 7.41–7.37 (m, 1 H), 7.28–7.24 (m, 3 H), 7.12–7.09 (m, 2 H), 3.83 (t, J = 7.1 Hz, 2 H), 2.80 (t, J = 7.2 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 166.2, 163.5 (d, J = 249.0 Hz), 138.9, 135.1, 130.8, 130.7 (d, J = 8.3 Hz), 128.6, 127.7, 127.5, 126.6, 115.1 (d, J = 22.0 Hz), 47.6, 26.3 ppm. HRMS: m/z calcd for C15H13NF [M + H]+: 226.1032; found: 226.1033. 3-(3,4-Dihydroisoquinolin-yl)benzonitrile (3o) Yield 0.15 g (65%), pale yellow oil. IR (film): 2943, 2230, 1611, 1568, 1310, 708 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.93–7.92 (m, 1 H), 7.87–7.85 (m, 1 H), 7.74–7.72 (m, 1 H), 7.56–7.53 (m, 1 H), 7.44–7.41 (m, 1 H), 7.31–7.26 (m, 2 H), 7.17–7.15 (m, 1 H), 3.87 (t, J = 7.2 Hz, 2 H), 2.82 (t, J = 7.3 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 165.4, 140.2, 138.7, 133.0, 132.7, 132.4, 131.2, 129.0, 127.9, 127.7, 127.2, 126.8, 118.4, 112.5, 47.8, 26.1 ppm. HRMS: m/z calcd for C16H13N2 [M + H]+: 233.1079; found: 233.1069. tert-Butyl [3-(3,4-Dihydroisoquinolin-1-yl)phenyl]-carbamate (3p) Yield 0.25 g (76%), yellow oil. IR (KBr): 3232, 2975, 1723, 1609, 1549, 1240, 1159, 777 cm–1. 1H NMR (500 MHz, DMSO-d 6): δ = 9.42 (s, 1 H), 7.74 (s, 1 H), 7.64–7.61 (m, 1 H), 7.56–7.53 (m, 1 H), 7.44 (t, J = 7.4 Hz, 1 H), 7.36–7.28 (m, 3 H), 7.16 (d, J = 7.5 Hz, 1 H), 7.10 (d, J = 7.5 Hz, 1 H), 3.71 (t, J = 7.2 Hz, 2 H), 2.73 (t, J = 7.2 Hz, 2 H) ppm. 13C NMR (125 MHz, DMSO-d 6): δ = 165.8, 152.9, 139.5, 139.3, 138.6, 130.8, 128.9, 128.4, 127.6, 127.3, 126.8, 122.4, 119.0, 118.3, 79.2, 47.1, 28.3, 25.8 ppm. HRMS: m/z calcd for C20H23N2O2 [M + H]+: 323.1760; found: 323.1743. 1-(2-Fluorophenyl)-3,4-dihydroisoquinoline (3s) 24 Yield 0.14 g (61%), yellow crystals, mp 79–80 °C (i-Pr2O). IR (KBr): 3444, 2946, 1612, 1447, 1210, 768 cm-1. 1H NMR (500 MHz, CDCl3): δ = 7.53–7.50 (m, 1 H), 7.44–7.36 (m, 2 H), 7.26–7.21 (m, 3 H), 7.13–7.07 (m, 2 H), 3.90 (br s, 2 H), 2.87 (br s, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 163.9, 161.1, 160.0, 159.1, 137.2, 130.9, 130.8, 130.7, 127.4, 127.0 (d, J = 15.1 Hz), 124.3 (d, J = 3.4 Hz), 115.8 (d, J = 22.0 Hz), 94.8, 47.8, 26.0 ppm. HRMS: m/z calcd for C15H13NF [M + H]+: 226.1032; found: 226.1031. 1,1′-Benzene-1,4-diyldi-3,4-dihydroisoquinoline (3t) Yield 0.04 g (23%), white crystals, mp 198–199 °C (MeCN). IR (KBr): 3421, 2942, 1603, 1315 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.66–7.62 (m, 4 H), 7.48–7.45 (m, 2 H), 7.39–7.38 (m, 2 H), 7.36–7.32 (m, 2 H), 7.25–7.24 (m, 2 H), 3.76 (br s, 4 H), 2.77 (br s, 4 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 165.5, 139.4, 138.7, 130.9, 128.5, 127.8, 127.2, 126.9, 47.3, 25.8 ppm. HRMS: m/z calcd for C24H21N2 [M + H]+: 337.1705; found: 337.1711.
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Figure 1 Structure of some important isoquinoline derivatives
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Scheme 1 Arylation of 1-(methylsulfanyl)-3,4-dihydroisoquinoline (1)
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Scheme 2 The reaction of 1-(methylsulfanyl)-3,4-dihydroisoquinoline (1) with 1,4-benzenediboronic acid (2t)
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Scheme 3 The arylation of 3,4-dihydroisoquinoline-1(2H)-thione (4)