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

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.

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

References

<A NAME="RG33102ST-1A">1a</A> Cimanga K. De Bruyne T. Pieters L. Claeys M. Vlietinck A. Tetrahedron Lett.  1996,  37:  1703 

<A NAME="RG33102ST-1B">1b</A> Sharaf MHM. Schiff PL. Tackie AN. Phoebe CH. Martin GE. J. Heterocycl. Chem.  1996,  33:  239 

<A NAME="RG33102ST-1C">1c</A> Pousset J.-L. Martin M.-T. Jossang A. Bodo B. Phytochemistry  1995,  39:  735 

<A NAME="RG33102ST-2A">2a</A> Grellier P. Ramiaramanana L. Millerioux V. Deharo E. Schrével J. Frappier F. Trigalo F. Bodo B. Pousset J.-L. Phytotherapy Res.  1996,  10:  317 

<A NAME="RG33102ST-2B">2b</A> Kirby GC. Paine A. Warhurst DC. Noamese BK. Phillipson JD. Phytotherapy Res.  1995,  9:  359 

<A NAME="RG33102ST-2C">2c</A> Cimanga K. De Bruyne T. Pieters L. Vlietinck A. Turger CA. J. Nat. Prod.  1997,  60:  688 

<A NAME="RG33102ST-3">3</A> Jonckers THM. Van Miert S. Cimanga K. Bailly C. Colson P. De Pauw M.-C. Lemière F. Esmans EL. Rozenski J. Quirijnen L. Maes L. Dommisse R. Lemière GLF. Vlietinck A. Pieters L. J. Med. Chem.  2002,  45:  3497 

For the synthesis of 11H-indolo[3,2-c]quinolines see:

<A NAME="RG33102ST-4A">4a</A> Arcadi A. Cacchi S. Cassetta A. Fabrizi G. Parisi LM. Synlett  2001,  1605 

<A NAME="RG33102ST-4B">4b</A> Mouaddib A. Joseph B. Hasnaoui A. Mérour J.-Y. Synthesis  2000,  549 

<A NAME="RG33102ST-4C">4c</A> Cacchi S. Fabrizi G. Pace P. Marinelli F. Synlett  1999,  620 

<A NAME="RG33102ST-4D">4d</A> Go M.-L. Ngiam T.-L. Tan AL.-C. Kuaha K. Wilairat P. Eur. J. Pharm. Sci.  1998,  6:  19 

<A NAME="RG33102ST-4E">4e</A> Molina A. Vaquero JJ. Garcia-Navio JL. Alvarez-Builla J. Pascual-Teresa B. Gago F. Rodrigo MM. Ballesteros M. J. Org. Chem.  1996,  61:  5587 

<A NAME="RG33102ST-4F">4f</A> Trécourt F. Mongin F. Mallet M. Quéguiner G. Synth. Commun.  1995,  25:  4011 

<A NAME="RG33102ST-4G">4g</A> Go ML. Ngiam TL. Phillipson JD. Kirby GC. O’Neill MJ. Warhurst DC. Eur. J. Med. Chem.  1992,  27:  301 

<A NAME="RG33102ST-4H">4h</A> Molina P. Alajarin M. Vidal A. Tetrahedron  1990,  46:  1063 

<A NAME="RG33102ST-4I">4i</A> Dave V. Warnhoff EW. Tetrahedron  1975,  31:  1255 

For recent reviews on the Buchwald-Hartwig reaction see:

<A NAME="RG33102ST-5A">5a</A> Barañano D. Mann G. Hartwig JF. Curr. Org. Chem.  1997,  1:  287 

<A NAME="RG33102ST-5B">5b</A> Frost CG. Mendonça P. J. Chem. Soc., Perkin Trans. 1  1998,  2615 

<A NAME="RG33102ST-5C">5c</A> Hartwig JF. Angew. Chem. Int. Ed.  1998,  37:  2046 

<A NAME="RG33102ST-5D">5d</A> Muci AR. Buchwald SL. Top. Curr. Chem.  2002,  219:  131 

For examples on intramolecular Pd-catalyzed arylation of N-(o-bromoazaheteroaryl)anilines and N-azaheteroaryl-2-bromoanilines see:

<A NAME="RG33102ST-6A">6a</A> Ames DE. Bull D. Tetrahedron  1982,  38:  383 

<A NAME="RG33102ST-6B">6b</A> Iwaki T. Yasuhara A. Sakamoto T. J. Chem. Soc., Perkin Trans. 1  1999,  1505 

<A NAME="RG33102ST-7">7</A> Just before submitting this manuscript an article appeared dealing with intramolecular Pd-catalyzed arylation of N-(2-chloroaryl)-N-methylanilines and N-benzyl-N-(2-chloroaryl)-anilines: Bedford RB. Cazin CSJ. Chem. Commun.  2002,  2310 

Several examples of the beneficial effect of the use of large excesses of inorganic bases in Pd-catalyzed aminations using Pd(BINAP) catalyst have already been reported by our research group:

<A NAME="RG33102ST-8A">8a</A> Komrlj J. Maes BUW. Lemière GLF. Haemers A. Synlett  2000,  1581 

<A NAME="RG33102ST-8B">8b</A> Jonckers THM. Maes BUW. Lemière GLF. Dommisse R. Tetrahedron  2001,  57:  7027 

<A NAME="RG33102ST-8C">8c</A> Maes BUW. Loones KTJ. Jonckers THM. Lemière GLF. Dommisse RA. Haemers A. Synlett  2002,  1995 

<A NAME="RG33102ST-9">9</A>

No attempts to reduce the excess of K₂CO₃ were performed.

<A NAME="RG33102ST-10">10</A> For the Pd-catalyzed amination of 2-chloroquinoline with ethyl 2-amino-4-phenyl-1,3-thiazole-5-carboxylate see: Yin J. Zhao MM. Huffman MA. McNamara JM. Org. Lett.  2002,  4:  3481 

<A NAME="RG33102ST-11">11</A> For the Ni-catalyzed amination of 2-chloroquinoline see: Desmarets C. Schneider R. Fort Y. J. Org. Chem.  2002,  67:  3029 

<A NAME="RG33102ST-12">12</A> For the S_NAr model of oxidative addition see: Fitton P. Rick EA. J. Organomet. Chem.  1971,  28:  287 

<A NAME="RG33102ST-13">13</A>

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

<A NAME="RG33102ST-14">14</A>

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

Tri-t-butylphosphine has already been used as an effective ligand in intermolecular Heck reactions of non-activated aryl chlorides with alkenes:

<A NAME="RG33102ST-15A">15a</A> Littke AF. Fu GC. J. Org. Chem.  1999,  64:  10 

<A NAME="RG33102ST-15B">15b</A> Ehrentraut A. Zapf A. Beller M. Synlett  2000,  1589 

<A NAME="RG33102ST-15C">15c</A> N,N-Dicyclohexyl-methylamine was found to be a superior base for intermolecular Heck reactions of non-activated aryl chloride substrates in comparison with inorganic bases: Littke AF. Fu GC. J. Am. Chem. Soc.  2001,  123:  6989 . Attempts to use 1.1 equiv of this amine in our intramolecular Pd-catalyzed arylation reaction on 10 gave no better result since starting material remained after 36 h heating

<A NAME="RG33102ST-16">16</A>

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.

<A NAME="RG33102ST-17">17</A>

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.

<A NAME="RG33102ST-18">18</A> Dubovitskii SV. Radchenko OS. Novikov VL. Russ. Chem. Bull.  1996,  45:  2657 

<A NAME="RG33102ST-19">19</A> Timári G. Soós T. Hajós G. Synlett  1997,  1067 

<A NAME="RG33102ST-20A">20a</A> Fresneda PM. Molina P. Delgado S. Tetrahedron Lett.  1999,  40:  7275 

<A NAME="RG33102ST-20B">20b</A> Fresneda PM. Molina P. Delgado S. Tetrahedron  2001,  57:  6197 

<A NAME="RG33102ST-21">21</A> While our work was in progress an article appeared dealing with a photochemical synthesis of isocryptolepine: Kumar RN. Suresh T. Mohan PS. Tetrahedron Lett.  2002,  43:  3327 

<A NAME="RG33102ST-22">22</A>

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): ν_max = 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.

<A NAME="RG33102ST-23">23</A>

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

<A NAME="RG33102ST-24">24</A>

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