α-Alkylation of N–C Axially Chiral Quinazolinone Derivatives Bearing Various ortho-Substituted Phenyl Groups: Relation between Diastereoselectivity and the ortho-Substituent

Published as part of the Cluster Atropisomerism

Dedicated to the late Professor Kurt Mislow with the deepest respect.

Abstract

2-Ethylquinazolin-4-one derivatives bearing various ortho-substituted phenyl groups were revealed to possess a stable C–N axially chiral structure at ambient temperature. The reactions of alkyl halides with the anionic species prepared from these quinazolinones were systematically explored. The α-alkylation reactions proceeded with diastereoselectivities ranging from 1:1 to >50:1, depending upon the steric bulk of the ortho-substituent, to afford products having the elements of axial and central chirality in high yields (85–98%).

Key words

axial chirality - quinazolinones - alkylation - diastereoselectivity

• References and Notes


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• 9 α-Alkylation of 3-(2-Bromophenyl)-2-ethylquinazolin-4-one (1c); Typical Procedure A 1.3 M solution of LiHDMS in THF (0.346 mL, 0.45 mmol) was added to a solution of rac-1c (99 mg, 0.3 mmol) in THF (2.0 mL) under N₂ at –20 °C, and the mixture was stirred for 30 min at –20 °C. Allyl bromide (54 mg, 0.45 mml) was added at –20 °C, and the mixture was stirred for 30 min at –20 °C. The mixture was then poured into saturated aq NH₄Cl solution (10 mL) and extracted with EtOAc (3 × 20 mL). The extracts were washed with brine, dried (MgSO₄), filtered, and evaporated to dryness. The residue was purified by column chromatography [silica gel, hexane–EtOAc (1:4)] to give a mixture of 2c and 2c′; yield: 94 mg (85%). The diastereomeric ratio of 2c and 2c′ (7.5:1) was determined by ¹H NMR analysis. 2c and 2c′ were completely separated by MPLC (hexane–EtOAc, 1:8) to give diastereomerically pure 2c and 2c′
  (P*,S*)-3-(2-Bromophenyl)-2-(1-methylbut-3-en-1-yl)quinazolin-4(3H)-one (2c) White solid; yield: 82 mg; mp 114–116 °C. IR (neat): 1684 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.29 (dd, J = 0.8, 7.6 Hz, 1 H), 7.73–7.80 (m, 3 H), 7.51 (dt, J = 1.6, 7.6 Hz, 1 H), 7.47 (ddd, J = 2.0, 6.8, 7.6 Hz, 1 H), 7.39 (dt, J = 1.6, 8.0 Hz, 1 H), 7.33 (dd, J = 1.6, 7.6 Hz, 1 H), 5.57 (tdd, J = 6.8, 10.8, 16.0 Hz, 1 H), 4.94 (d, J = 10.8 Hz, 1 H), 4.94 (d, J = 16.0 Hz, 1 H), 2.41–2.56 (m, 2 H), 2.20 (td, J = 6.8, 13.6 Hz, 1 H), 1.33 (d, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 161.8, 159.8, 147.7, 136.7, 135.5, 134.6, 133.8, 130.7, 128.6, 127.3, 127.0, 126.5, 123.3, 120.6, 117.2, 40.4, 37.9, 18.9. MS: m/z = 391 [M + Na]⁺ (⁷⁹Br); HRMS: m/z [M + Na]⁺Calcd for C₁₉H₁₇ ⁷⁹BrN₂NaO: 391.04220; found: 391.04207. (P*,R*)-3-(2-Bromophenyl)-2-(1-methylbut-3-en-1-yl)quinazolin-4(3H)-one (2c′) White solid; yield: 12 mg; mp 78–80 °C. IR (neat): 1680 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.28 (dd, J = 1.6, 8.0 Hz, 1 H), 7.73–7.81 (m, 3 H), 7.51 (dt, J = 1.2, 7.2 Hz, 1 H), 7.47 (ddd, J = 1.2, 7.2, 8.4 Hz, 1 H), 7.40 (dt, J = 2.0, 8.0 Hz, 1 H), 7.35 (dd, J = 2.0, 8.0 Hz, 1 H), 5.71 (m, 1 H), 5.04 (d, J = 17.2 Hz, 1 H), 4.97 (d, J = 10.0 Hz, 1 H), 2.75 (m, 1 H), 2.31–2.40 (m, 2 H), 1.17 (d, J = 6.4 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 161.8, 160.0, 147.6, 136.6, 136.2, 134.6, 133.9, 130.8, 130.2, 128.7, 127.3, 127.1, 126.6, 123.3, 120.6, 117.0, 39.1, 38.0, 19.4. MS: m/z = 391 [M + Na]⁺ (⁷⁹Br); HRMS: m/z [M + Na]⁺Calcd for C₁₉H₁₇ ⁷⁹BrN₂NaO: 391.04220; found: 391.04071.