Preparation of Isoindolones by a Lithium-Iodide Exchange-Induced Intra­molecular Wurtz-Fittig Reaction of o-Iodobenzoyl Chloride/Imine Adducts

Abstract

Addition of o-iodobenzoyl chlorides to imines affords N-acyliminium ions, perhaps in equilibrium with α-chlorobenz­amides, as adducts. Reaction of the adducts with 1.1 equivalents of phenyllithium at -78 ˚C followed by warming to ambient temperature induces an intramolecular Wurtz-Fittig coupling to afford 2,3-dihydroisoindolones in excellent yields.

Key words

metal-halogen exchange - Wurtz-Fittig - isoindolone - imines - acid chloride

References and Notes

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  Enders surveys the literature by systematically considering multiple retrosynthetic disconnects for assembling isoindolones. Using his nomenclature from the aforementioned citation, Method II and Method VIII would involve the formation of a bond between the carbon α to nitrogen and the ortho-C-aryl carbon (red bond designated in Scheme  [¹] , structure 5).

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• 19a

  General Procedure for the Synthesis of Isoindolones 5 from o -Iodobenzoyl Chlorides 1 and Imines 2: Neat 2-iodobenzoyl chloride (1 mmol) was added dropwise to a solution of the corresponding imine (1 mmol) as a solution in THF at -25 ˚C. After stirring for 10 min, the reaction was cooled to -78 ˚C and stirred for an additional 30 min. Phenyllithium (1.1 mmol, typically about 1.8 M in Et₂O-hexanes) was added dropwise to the solution over 5 min followed by stirring the reaction for 1 h at -78 ˚C. The cooling bath was removed, the reaction warmed to ambient temperature, then stirred for 1 h. The reaction was quenched slowly at ambient temperature by the addition of H₂O. The mixture was stirred for about 30 min, followed by extraction of the mixture with CH₂Cl₂. The combined extracts were dried (Na₂SO₄), concentrated and chromatographed by flash chromatography. The isolated products were typically obtained as viscous oils. Several of the products (designated in Table  [¹] ) were distilled in a bulb-to-bulb short path (Kugelrohr) distillation apparatus. [Note: Imines were prepared by one of two procedures. For volatile imines, a procedure using K₂CO₃ reported by Stork et al.^¹9b was followed. Imines were distilled and then stored under a nitrogen atmosphere at 0 ˚C prior to use. For non-volatile imines, the procedure using dibutyltin dichoride and Na₂SO₄ as described by Stetin et al.^¹9c was followed. The imines were isolated and used immediately without further purification]

• 19b Stork G. Dowd SR. Org. Synth.  1974,  54:  46 
• 19c Stetin C. de Jeso B. Pommier JC. Synth. Commun.  1982,  12:  495 

10

At -78 ˚C formation of the acid chloride/imine adduct was considerably slower with the yields of isoindolone 4 dropping significantly.

20

Spectroscopic and characterization data for selected products: 2-Butyl-3-propyl-2,3-dihydroisoindol-1-one (5a): ^¹H NMR (300 MHz, CDCl₃): δ = 0.82 (m, 4 H), 0.95 (t, 3 H, J = 7.3 Hz), 1.08 (m, 1 H), 1.37 (m, 2 H), 1.60 (m, 2 H), 1.93 (m, 2 H), 3.08 (m, 1 H), 4.02 (dt, 1 H, J = 8.0, 13.9 Hz), 4.59 (t, 1 H, J = 3.8 Hz), 7.46 (m, 3 H), 7.83 (d, 1 H, J = 7.4 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ = 13.72, 13.96, 15.76, 20.09, 30.38, 32.60, 39.36, 58.87, 121.90, 123.41, 127.41, 127.85, 131.03, 132.76, 145.16, 168.36. MS: m/z = 232 [M + H]. Anal. Calcd for C₁₅H₂₁NO˙0.25 H₂O: C, 76.39; H, 9.19; N, 5.93. Found: C, 76.20; H, 8.82; N, 5.95. 2-Butyl-3-propyl-6-bromo-2,3-dihydroisoindol-1-one (5b): ^¹H NMR (300 MHz, CDCl₃): δ = 0.85 (m, 4 H), 0.94 (t, 3 H, J = 7.4 Hz), 1.08 (m, 1 H), 1.36 (m, 2 H), 1.61 (m, 2 H), 1.92 (m, 2 H), 3.08 (m, 1 H), 4.00 (dt, 1 H, J = 8.0, 13.9 Hz), 4.56 (t, 1 H, J = 3.7 Hz), 7.29 (d, 1 H, J = 8.1 Hz), 7.63 (d, 1 H, J = 8.1 Hz), 7.96 (s, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 13.76, 13.97, 15.70, 20.13, 30.35, 32.45, 39.57, 58.75, 122.00, 123.61, 126.69, 134.04, 134.91, 143.84, 166.90. MS: m/z = 310, 312 [M + H]. Anal. Calcd for C₁₅H₂₀NOBr: C, 58.07; H, 6.50; N, 4.51. Found: C, 57.76; H, 6.47; N, 4.60. 2-Benzyl-3-cyclohexyl-2,3-dihydroisoindol-1-one (5e): mp 163-164.5 ˚C (methyl tert-butyl ether-hexanes). ^¹H NMR (300 MHz, CDCl₃): δ = 0.42 (m, 1 H), 1.06 (m, 2 H), 1.26 (m, 2 H), 1.43 (m, 2 H), 1.68 (m, 2 H), 2.03 (m, 1 H), 3.10 (m, 1 H), 4.20 (d, 1 H, J = 15.2, 13.9 Hz), 4,26 (d, 1 H, J = 3.1 Hz), 5.40 (d, 1 H, J = 15.2 Hz), 7.35 (m, 5 H), 7.45 (m, 3 H), 7.90 (d, 1 H, J = 6.45 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ = 25.76, 25.95, 26.35, 26.90, 29.69, 39.38, 43.98, 63.57, 123.27, 123.77, 127.46, 127.93, 128.06, 128.66, 128.90, 130.92, 132.82, 137.17, 144.09, 168.68. MS: m/z = 306 [M + H]. Anal. Calcd for C₂₁H₂₃NO: C, 82.58; H, 7.59; N, 4.85. Found: C, 82.11; H, 7.53; N, 5.14. 2-[2-(1,3-Dioxolan-2-yl)ethyl]-3-propylisoindolin-1-one (5g): ^¹H NMR (300 MHz, CDCl₃):
δ = 0.83 (m, 4 H), 1.07 (m, 1 H), 1.98 (m, 4 H), 3.25 (m, 1 H), 3.85 (m, 2 H), 3.99 (m, 2 H), 4.12 (m, 1 H), 4.64 (m, 1 H), 4.93 (m, 1 H), 7.42 (m, 3 H), 7.81 (d, 1 H, J = 7.4 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ = 13.95, 15.67, 32.41, 32.57, 35.09, 59.17, 64.89, 102.57, 121.96, 123.39, 127.84, 131.12, 132.64, 145.26, 168.38. MS: m/z = 276 [M+]. Anal. Calcd for C₁₆H₂₁NO₃: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.52; H, 7.57; N, 5.30. 2-Propyl-3-(2-furyl)-2,3-dihydroisoindol-1-one (5h): ^¹H NMR (300 MHz, CDCl₃): δ = 0.90 (t, 3 H,
J = 7.4 Hz), 1.57 (m, 2 H), 3.08 (m, 1 H), 3.80 (dt, 1 H, J = 7.4, 12.2 Hz), 5.60 (s, 1 H), 6.31 (d, 1 H, J = 3.2 Hz), 6.37 (dd, 1 H, J = 3.2, 1.6 Hz), 7.35 (m, 1 H), 7.47 (d, 1 H, J = 1.6 Hz), 7.50 (m, 2 H), 7.88 (m, 1 H). MS: m/z = 242 [M + H].

21

By comparison the procedure described in this manuscript provides isoindolones in comparable yields and purity to our previously described work.⁸ For larger scale reactions, the present work is more practical to conduct requiring temperatures no lower than -78 ˚C.