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Synlett 2003(5): 0615-0618
DOI: 10.1055/s-2003-38364
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Isocryptolepine via a Pd-Catalyzed ‘Amination-Arylation’ Approach

Tim H. M. Jonckersa, Bert U. W. Maes*a, Guy L. F. Lemièrea, Geert Romboutsa, Luc Pietersb, Achiel Haemersb, Roger A. Dommissea
a Department of Chemistry, University of Antwerp (RUCA), Groenenborgerlaan 171, 2020 Antwerp, Belgium
Fax: +32(3)2180233; e-Mail: bert.maes@ua.ac.be;
b Department of Pharmaceutical Sciences, University of Antwerp (UIA), Universiteitsplein 1, 2610 Antwerp, Belgium
Further Information

Publication History

Received 9 December 2002
Publication Date:
28 March 2003 (online)

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Abstract

Isocryptolepine (cryptosanguinolentine) has been synthesized in three steps via a new approach starting from commercially available 4-chloroquinoline and 2-chloroaniline. The new methodology consists of two consecutive palladium-catalyzed reactions; a selective Buchwald-Hartwig amination followed by an intramolecular arylation reaction.

Key words

palladium - Buchwald-Hartwig amination - intramole­cular arylation - isocryptolepine - malaria

9

No attempts to reduce the excess of K2CO3 were performed.

13

2-(Dicyclohexylphosphino)biphenyl, 2-(di-t-butyl-phosphino)biphenyl and tri-t-butylphosphine are commercially available from Strem Chemicals.

14

Tripotassium phosphate (minimum 98%) was obtained from Sigma (catalogue number: P-5629). The pellets were finely grinded in a mortar.

16

Most probably an interphase mechanism is acting since the large excess of base used in the Pd-catalyzed reaction does not dissolve in the solvent used. The insoluble excess speeds up these Pd-catalyzed reactions by supplying a higher surface area.

17

When only 2 equiv of K3PO4 were used for the intramolecular Pd-catalyzed arylation reaction on 10 (20 mol% catalyst) and 6 (5 mol% catalyst), starting material remained after 36 h and 3 h heating in a pressure tube respectively. The use of 5 equiv of K3PO4 for the cyclodehydrohalogenation of 10 gave similar results as with 10 equiv while the cyclization of 6 gave a significant rate decrease in comparison with the reference experiment where 10 equiv of base were used.

22

4-(2-Chlorophenylamino)quinoline ( 6):
A round bottom flask was charged with Pd2(dba)3 (0.0274 g, 0.03 mmol, 1 mol%), XANTPHOS (0.0385 g, 0.066 mmol, 2.2 mol%), 4-chloroquinoline (0.490 g, 3 mmol), 2-chloroaniline (0.459 g, 3.6 mmol), Cs2CO3 (1.368 g, 4.2 mmol) and dry dioxane (12 mL) (freshly distilled). The resulting mixture was flushed with N2 for 15 min and subsequently refluxed overnight in an oil bath under a N2 atmosphere with magnetic stirring. After cooling down, the solid material was filtered off and washed well with CH2Cl2 (300 mL). The filtrate was evaporated and the resulting crude product was purified by flash column chromatography on silicagel using EtOAc-MeOH (85:15) as the eluent. Yield: 81%; white solid; mp 140.0 °C. IR (KBr): νmax = 3141, 3061, 2908, 1592, 1570, 1531, 1476, 1441, 1391, 1335, 1244, 1051, 899, 819, 811, 761, 747, 588 cm-1. 1H NMR (CDCl3): δ = 6.87 (br s, 1 H, NH), 7.06 (d, 1 H, J = 5.19 Hz, H-3), 7.09 (ddd, 1 H, J = 9.01 Hz, J = 7.48 Hz, J = 1.53 Hz, H-4′), 7.31 (ddd, 1 H, J = 9.01 Hz, J = 7.48 Hz, J = 1.53 Hz, H-5′), 7.50 (dd, 1 H, J = 8.09 Hz, J = 1.53 Hz, H-6′), 7.54 (dd, 1 H, J = 8.09 Hz, J = 1.52 Hz, H-3′), 7.57 (ddd, 1 H, J = 8.24 Hz, J = 6.86 Hz, J = 1.22 Hz, H-6), 7.73 (ddd, 1 H, J = 8.40 Hz, J = 7.32 Hz, J = 1.38 Hz, H-7), 8.02 (dd, 1 H, J = 8.40 Hz, J = 0.92 Hz, H-5), 8.10 (d, 1 H, J = 8.09 Hz, H-8), 8.64 (d, 1 H, J = 5.34 Hz, H-2). 13C NMR (CDCl3): δ = 103.8, 119.8, 120.5, 121.4, 124.3, 125.7, 125.8, 127.6, 129.5, 130.2, 130.3, 137.2, 145.9, 149.3, 150.8. LRMS (DCI): 255.

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11 H -Indolo[3,2- c ]quinoline ( 7): A round bottom flask was charged with Pd2(dba)3 (0.0458 g, 0.05 mmol, 2.5 mol%), followed by dry dioxane (20 mL) (freshly distilled). To this solution (t-Bu)3P (0.5 mL, 0.4 M solution in toluene, 0.2 mmol, 10 mol%) was added via a syringe. The resulting mixture was stirred for 15 min under Ar. Meanwhile, 4-(2-chlorophenylamino)quinoline (0.509 g, 2 mmol) and finely grinded K3PO4 (4.246 g, 20 mmol) were weighed in a pressure tube. To this solid mixture, the Pd-catalyst was added and the flask was rinsed well with an additional 20 mL of dioxane which was also added to the tube. The resulting mixture was flushed with Ar for several minutes. Subsequently, the tube was closed and heated for 3 h at 120 °C under vigorous magnetic stirring. After cooling down to r.t. the tube was opened and the crude reaction mixture was filtered through a pad of Celite which was rinsed with CH2Cl2 (240 mL). Column chromatography on silicagel using EtOAc-MeOH (85:15) as the eluent gave the title compound in 95% yield. The characterization data of 7 were identical with those reported in the literature.18

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Isocryptolepine (5-methyl- 5H -indolo[3,2- c ]quinoline) (1): In a round bottom flask 11H-indolo[3,2-c]quinoline (0.141 g, 0.646 mmol), DMF (5 mL) and CH3I (1 mL) were heated at 80 °C for 1 h under magnetic stirring, and subsequently left at r.t. overnight. Then, aq Na2CO3 (2 M, 10 mL) was added to the reaction mixture and stirred for 5 min. The mixture was extracted with CH2Cl2 (3 ¥ 60 mL). The organic layer was dried on MgSO4, filtered and the solvent removed under vacuum. The crude product was purified via column chromatography on silica gel [eluent: CH2Cl2-MeOH (8:2) followed by NH3 (7 M in MeOH)] giving the title compound in 75% yield. The characterization data of 1 were identical with those reported in the literature.1b