Iridium-Catalyzed Enantioselective Allylic Substitutions with Aliphatic Nitro Compounds as Prenucleophiles

Abstract

Enantioselective Ir-catalyzed allylic alkylations with nitroalkanes and ethyl nitroacetate as nucleophiles are reported. Up to 99% ee was achieved using catalysts prepared by in situ activation of mixtures of phosphorus amidites and [Ir(COD)Cl]₂. The method was applied to a synthesis of the antidepressant (1S,2R)-trans-2-phenylcyclopentanamine.

Key words

allylic substitution - iridium - catalysis - nitroalkanes - ring-closing metathesis

References and Notes

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• 21a

  The absolute configuration of 9 was assigned by comparison of HPLC data of the N-isopropylsulfonyl derivative of 9 with reported data (ref. 16) and on the basis of the optical rotation of (1S,2R)-9·HCl (93%ee): [α]_D ²⁰ +56.6; reported: [α]_D ²³ +68.8 (99% ee), see ref. 21b. The ee of 9 was determined by HPLC; column: Daicel Chiracel OD-H, 250 × 4.6 mm, 5 µm, and guard cartridge 10 × 4 mm, 5 µm; eluent: n-hexane-i-PrOH, 99:1; flow: 0.5 mL/min; t _R [(1S,2R)-9] = 36.9 min, t _R [(1R,2S)-9] = 40.6 min.

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2

Contrary to common believe, the prize of iridium is lower than that of palladium.

9

General Procedure for Allylic Alkylation Under argon at r.t., a solution of [Ir(COD)Cl]₂ (0.02 mmol) and L* (0.04 mmol) in dry THF (1.0 mL) was treated with TBD (0.08 mmol). After stirring for 2 h at r.t. the allylic carbonate (1.0 mmol) was added, and the mixture was stirred for 5 min at r.t. Then the nitro compound (1.5 mmol) and eventually Cs₂CO₃ (1.0 mmol) were added and the mixture was stirred until GCMS indicated complete conversion. The mixture was partitioned between H₂O and EtOAc. The organic layer was dried over Na₂SO₄ and concentrated in vacuo. The residue was analyzed with respect to the content of branched and linear product by ¹H NMR. The pure reaction products were obtained by flash chromatography and kugelrohr distillation.

13

General Procedure for the Preparation of Primary Nitro Compounds 5 from Esters 3 (Scheme 4) Under argon, a solution of ester 3, LiI (5 equiv), H₂O (6 equiv) and a trace of di-tert-butyl-1,4-hydroquinone in DMF was heated at 150 °C over a period of 5 h. Then, sat. NaCl solution was added and the mixture was extracted with Et₂O. The combined organic layers were dried over Na₂SO₄, concentrated in vacuo, and the residue was subjected to flash chromatography.

17

Both enantiomers of 6 were prepared. The ee was obtained after transformation to 7a. The ee of the latter was determined by HPLC; column: Daicel Chiralcel OJ-H,
250 × 4.6 mm, 5 µm, and guard cartridge 10 × 4 mm, 5 µm; eluent: n-hexane-i-PrOH, 90:10; flow: 0.5 mL/min;
t _R [(-)-7a] = 23.5 min, t _R [(+)-7a] = 29.9 min (major).