An Intramolecular Heck Reaction that Prefers a 5-endo- to a 6-exo-trig
Cyclization Pathway

Abstract

A regioselective aromatic Claisen rearrangement was used to prepare 17a, the precursor of triflate 17e. The intramolecular Heck reaction of 17e is promoted only by bidentate phosphine ligands, giving exclusively and in excellent yield 20, the product of a 5-endo-trig cyclization, despite the possibility for a 6-exo-trig pathway.

Key words

intramolecular Heck reaction - 5-endo-trig cyclization - regioselective Claisen rearrangement

References and Notes

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  For a recent and interesting approach towards the core of the teleocidins B, see:

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  Addition of silver salts to the reaction mixture often allows the use of aryl and vinyl halides in AIHR, see ref. 6.

• 8b For a notorious example of IAHR where the ‘neutral’ pathway affords higher enantioselectivity than the corresponding ‘cationic’, see: Overman LE. Poon DJ. Angew. Chem., Int. Ed. Engl.  1997,  36:  518 
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  See ref. 6.

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3

The numbering system of teleocidins is defined in the following order of preference: the indole ring, the nine-membered lactam ring, and the other substituents.

16

Procedure for the Preparation of 17a.
A solution of indole 13 (1.42 g, 4.16 mmol, 1.0 equiv), HMDS (8.7 mL, 41.8 mmol, 10 equiv) and dimethylaniline (30 mL) in a closed, thick-wall glass container was inserted in a salt bath (53% KNO₃, 40% NaNO₂ and 7% NaNO₃, by weight) at 195 °C until TLC showed no more starting material (aprox. 6-7 h). After reaching r.t., the reaction mixture was partitioned between Et₂O (150 mL) and 3 M aq HCl (150 mL); the organic layer was further washed with 3 M aq HCl (100 mL), aq NaHCO₃ (two portions of 120 mL), brine (50 mL) and dried (Na₂SO₄). The solvent was removed under reduced pressure to afford a tan-colored oil, which was dissolved in EtOH (20 mL). The resulting solution was cooled to ice-bath temperature and treated with 3 M aq HCl (2.5 mL). After approx. 10 min, the reaction mixture was diluted with Et₂O (90 mL), washed with aq NaHCO₃ (two portions of 40 mL), brine (20 mL) and dried (Na₂SO₄). The resulting solution was concentrated under vacuum to approx. 1/5 of its original volume and eluted/filtered through a short column of silica gel using hexane-Et₂O (2:1). Rearranged indole 17a (1.25 g, 88%) was obtained as a thick, light-tan-colored oil. ¹H NMR (300 MHz, CDCl₃): δ = 9.38 (br s, 1 H), 7.41 (d, J = 8.5 Hz, 1 H), 7.11 (d, J = 2.1 Hz, 1 H), 6.67 (d, J = 8.5 Hz, 1 H), 6.57 (dd, J = 17.8, 10.8 Hz, 1 H), 5.63 (s, 1 H), 5.43 (d, J = 17.8 Hz, 1 H), 5.41 (d, J = 10.8 Hz, 1 H), 5.07 (m, 1 H), 4.37 (q, J = 7.1 Hz, 2 H), 2.18-1.76 (m, 4 H), 1.70 (s, 3 H), 1.62 (s, 3 H), 1.44 (s, 3 H), 1.40 (t, J = 7.1 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 162.2, 153.0, 148.7, 137.3, 131.9, 126.1, 124.5, 123.8, 122.1, 114.5, 113.3, 113.1, 108.7, 61.0, 45.5, 39.9, 25.9, 25.6, 24.0, 17.4, 14.7.

19

The structures were optimized at the B3LYP/6-31G* level of theory in Jaguar v. 4.2 from Scrödinger Inc., www.schrodinger.com. The conformations were chosen to represent the immediate product from a chair transition state, as expected for a Claisen rearrangement.

25

Typical Procedure for the Preparation of 20.
A mixture of indole 17e (50 mg, 0.1 mmol, 1.0 equiv), Pd(OAc)₂ (2.5 mg, 0.01 mmol, 10 mol%), K₂CO₃ (44 mg, 0.3 mmol, 3.0 equiv), and the ligand (0.03 mmol, 30 mol%) in degassed THF (2.1 mL) was refluxed for the time shown in Table [2] . After cooling to r.t., H₂O (2 mL) was added and the mixture was partitioned between Et₂O (15 mL) and H₂O (10 mL). The organic layer was washed with brine (5 mL), dried (MgSO₄) and concentrated under vacuum. The obtained residue was purified by flash chromatography (hexane-ether, 2:1) to afford cyclopentadieno-indole 20 as a faint yellow oil. ¹H NMR (300 MHz, CDCl₃): δ = 8.63 (br s, 1 H), 7.58 (dd, J = 0.75, 8.1 Hz, 1 H), 7.29 (d, J = 2.0 Hz, 1 H), 7.19 (d, J = 8.1 Hz, 1 H), 6.78 (d, J = 5.4 Hz, 1 H), 6.39 (d, J = 5.4 Hz, 1 H), 4.94 (m, 1 H), 4.43 (q, J = 7.1 Hz, 2 H), 2.10-1.59 (m, 4 H), 1.55 (br s, 3 H), 1.44 (s, 3 H), 1.43 (t, J = 7.1 Hz, 3 H), 1.36 (br s, 3 H).). ¹³C NMR (75 MHz, CDCl₃): δ = 162.5, 144.7, 141.4, 134.1, 132.7, 131.9, 130.1, 127.6, 126.7, 124.4, 121.4, 116.1, 109.9, 61.2, 54.1, 38.0, 25.8, 23.9, 22.8, 17.7, 14.7.