Ring Opening of Cyclic Sulfamidates with Magnesiated Heterocycles: Expedient Synthesis of Highly Functionalised Azaindolines and Azatetrahydroquinolines

Abstract

Magnesiated chloropyrimidine and chloropyridine derivatives, obtained by deprotonation with TMPMgCl⋅LiCl at room temperature, undergo facile ring-opening reactions with five- and six-membered N-Boc and N-Bn cyclic sulfamidates. After an acidic workup, the adducts undergo rapid intramolecular cyclisation on basification to give highly functionalised stereodefined aza­indolines and azatetrahydroquinolines in good yields.

Key words

cyclic sulfamidate - metalation - ring opening - pyrimidine - azaindoline

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• 16 Representative Procedure for the Synthesis of Azaindoline 12: To an oven-dried three-necked flask containing 4,6-dichloro-2-(thiomethyl)pyrimidine (1; 390 mg, 2.0 mmol) in anhyd THF (7.5 mL) was added TMPMgCl⋅LiCl (1 M in THF, 2.4 mL, 2.4 mmol) at r.t. After stirring for 30 min, tert-butyl (4S)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (5; 498 mg, 2.10 mmol) was added and the reaction was stirred for a further 1 h at r.t. 1 N Citric acid (7.5 mL) and EtOAc (7.5 mL) were added, and the reaction was stirred vigorously for 5 min before separation of the layers. The organic layer was concentrated, then the residue was stirred in TFA (5 mL) for 15 min before again being concentrated. [Note: Alternatively, TFA (7.5 mL) and H₂O (1 mL) can be added directly to the reaction mixture to cleave the sulfamic acid intermediate and N-Boc group in one process.] The residue was dissolved in MeCN (20 mL) and Et₃N (1.12 mL, 8.0 mmol) was added. The reaction was warmed to 80 °C for 30 min to effect cyclisation. The volatiles were removed under vacuum and the residue was purified by silica gel chroma-tography [heptane–EtOAc, 95:5 → 80:20] to give (R)-4-chloro-6-methyl-2-(methylthio)-6,7-dihydro-5H-pyrollo[2,3-d]pyrimidine (12) as a colourless solid (354.5 mg, 82%); mp 192–193 °C. IR: 3350 (w), 2985 (m), 1180 (s), 1045 (s), 885 (m) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 6.83 (s, 1 H, NH), 4.16 (m, 1 H, CHMe), 3.19 (dd, 1 H, J = 9.5, 16.8 Hz, CH ^aH^b), 2.59 (dd, 1 H, J = 5.8, 16.8 Hz, CH^a H ^b), 2.49 (s, 3 H, SMe), 1.37 (d, 3 H, J = 6.3 Hz, Me). ¹³C NMR (100 MHz, CDCl₃): δ = 170.76, 167.86, 151.43, 112.20, 51.86, 33.17, 23.11, 14.14. MS (EI): m/z = 216 (100) [M + H]⁺. HRMS (EI): m/z [M + H]⁺ calcd for C₈H₁₁N₃ClS: 216.03567; found: 216.03557