New methods for the synthesis of naphthyl amines ; application to the synthesis of dihydrosanguinarine , sanguinarine , oxysanguinarine and ( )-maclekarpines B and C †

We have recently reported the results of a programme of research aimed at expanding methods for the de novo construction of aromatic rings from linear precursors. When we consider the opportunities that exist for functionalisation of the non-aromatic intermediates produced en-route to an arene, and the potential for cross coupling and C–H activation on the aromatic products, then an attractive situation emerges. One of our previous endeavours focussed on preparing benzenoid compounds from unsaturated 1,5 dicarbonyls A and amines by using enamine chemistry (Scheme 1, the geometry and position of the alkene between the carbonyls is unimportant). We consider that both Mannich and electrocyclic based mechanisms are feasible for this transformation. Recently, we wanted to examine if this method might be extended to allow the formation of naphthyl amines via reaction of a keto-aldehyde containing an aromatic spacer, see B. As an additional objective, we also wanted to explore the possibility of adding extra functionality onto the cyclisation product and forming another ring onto the new aromatic system. This tactic is expected to greatly increase the utility of the method in the area of natural products synthesis. In the first instance, we used a combination of enolate arylbromide cross coupling reactions and alkene oxidative cleavage to prepare a set of three keto-aldehyde precursors (1–3) on which to test our hypotheses, Scheme 2. The cyclisation of

General Procedure 1 for palladium-catalysed α-arylation of ketones (DtBPF)PdCl 2 (5.0 mol%) and NaOtBu (250 mol%) were sealed in a dry microwave vial and the vial sealed.Aryl halide (100 mol%) was dissolved in THF (0.2 M with respect to ketone) and the resulting solution was added via syringe to the tube at room temperature.The ketone (200 mol%) was then added via syringe to the tube.The tube was then heated to 70 °C for 18 h.The reaction was then cooled to room temperature and quenched by the addition of H 2 O.
The aqueous layer was extracted with Et 2 O and the combined organics were dried (Na 2 SO 4 ), filtered and the solvent removed in vacuo to give the crude product which was purified under the conditions noted.
General Procedure 2 for deprotection of acetal para-Toluenesulfonic acid monohydrate (10 mol%) was added to a solution of the acetal substrate (100 mol%) in THF/H 2 O (1:1, 0.1 M with respect to acetal) in a microwave vial and the vial sealed.The tube was heated to 60 °C for 18 h then cooled to room temperature.Saturated aqueous NaHCO 3 was added and the aqueous layer extracted with EtOAc (3x) and the combined organics dried over Na 2 SO 4 , filtered and the solvent removed in vacuo to give the crude product, which was purified as specified.

General Procedure 3 for Lewis acid cyclisation to form napthyl amine
A microwave vial fitted with a magnetic follower was charged with the corresponding 1,5dicarbonyl (100 mol%) and ZnCl 2 (1.0 M in Et 2 O, 100 mol%), dissolved in CH 2 Cl 2 (0.10 M with respect to 1,5-dicarbonyl) and the corresponding amine (500 mol%) added.The reaction mixture was heated at 55 °C for 18 h and then cooled to room temperature.The crude mixture was concentrated and purified by flash column chromatography, under the conditions noted to afford the corresponding napthyl amine.

General Procedure 4 for acid cyclisation to form napthyl amine
A microwave vial fitted with a magnetic follower was charged with the corresponding 1,5dicarbonyl (100 mol%), dissolved in PhMe/AcOH 3:1 (0.10 M with respect to 1,5-dicarbonyl) and the corresponding amine (500 mol%) added carefully.The reaction mixture was heated at 110 °C for 18 h and then cooled to room temperature.The crude mixture was washed with 1.0 M NaOH (20 mL/mmol) and extracted into EtOAc (3x).The organic layers were combined, dried (MgSO 4 ) and concentrated.The crude product was purified by flash column chromatography, under the conditions noted to afford the corresponding napthyl amine.

3-Methyl-1H-indene, S1
CeCl 3 (4.23 g, 11.4 mmol) was heated at 130 °C under a high vacuum for 2 h.THF (50 mL) was added and the reaction stirred for 90 min at rt.The reaction was cooled for −78 °C and then MeLi (7.13 mL, 1.6 M in Et 2 O, 11.4 mmol) added and stirred for 30 min.A solution of indanone (1.00 g, 7.58 mmol) in THF (2 mL) was added dropwise and the resulting solution stirred for 1 h, then allowed to warm to rt.The reaction mixture was quenched by the addition of saturated aqueous NH 4 Cl then the THF removed in vacuo.The mixture was then partitioned between Et 2 O and water and the organic layer separated.The aqueous layer was washed with Et 2 O (2 x 100 mL), the organic layers combined, dried (MgSO 4 ), filtered and concentrated.The residue was dissolved in CH 2 Cl 2 (50 mL) and para-toluenesulfonic acid monohydrate (72 mg, 0.38 mmol) added.The reaction was stirred for 30 min, then concentrated and purified by flash column chromatography (petrol) to give indene S1 (845 mg, 86%).
The flask was equipped with a Dean-Stark apparatus and the solution heated to reflux for 18 h.The reaction mixture was cooled to rt and quenched by the addition of saturated aqueous NH 4 Cl and extracted with EtOAc (3 × 100 mL).The organic extracts were combined and extracted with brine (100 mL), dried (Na 2 SO 4 ) and concentrated in vacuo.Purification by flash column chromatography (petrol-EtOAc, 19:1) afforded acetal S3 (2.19 g, 90%) as a colourless oil.

Maclekarpine B, (23) and maclekarpine C, (24)
To a solution of diisopropyl amine (6 mg, 0.04 mmol) in THF (0.7 mL) at −78 °C was added nBuLi (0.15 mL, 0.43 mmol, 2.5 M in hexanes).The reaction was allowed to warm to rt and stirred for 10 min.The solution was then cooled to −78 °C and a suspension of sanguanine (10 mg, 0.03 mmol) (21) added dropwise.The solution was allowed to stir for a further 30 min then warmed to rt.The reaction was quenched by the addition of a saturated solution of NH 4 Cl and extracted into EtOAc (3 x 5 mL).
1 H NMR (400 MHz, CHLOROFORM-d)  ppm 8.32 (1 H, d, J=8.3 Hz), 8.10 (1 H, d, J=8.3 Cl and the THF removed in vacuo.The aqueous layer was extracted with Et 2 O (3 x 100 mL) and the organic layers combined, dried (MgSO 4 ) and concentrated to give crude alcohol which was dissolved in CH 2 Cl 2 and pyridinium p-toluenesulfonate (71 mg, 0.28 mmol) added.The reaction was stirred for 30 min at rt and concentrated in vacuo.The crude residue was purified by flash column chromatography (petrol-EtOAc, 19:1) to give alkene 11 (761 mg, 77 %) as a tan solid.
Position   H lit.      C lit.   C    H lit.      C lit.   C 