Synlett 2010(20): 3008-3010  
DOI: 10.1055/s-0030-1259061
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

James B. Campbell*, Robert F. Dedinas, Sally Trumbower-Walsh
Lead Generation Department, CNS Discovery, AstraZeneca Pharmaceuticals, Wilmington, DE 19850-5437, USA
Fax: +1(302)8851453; e-Mail: campbelljim.jbc@gmail.com;
Further Information

Publication History

Received 12 October 2010
Publication Date:
24 November 2010 (online)

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.

    References and Notes

  • 1a Bohme H. Hartke K. Chem. Ber.  1963,  96:  600 
  • 1b Bose AK. Spiegelman G. Manhas MS. Tetrahedron Lett.  1971,  3167 
  • 2a Speckamp WN. Hiemstra H. Tetrahedron  1985,  41:  4367 
  • 2b Arndtsen BA. Black DA. J. Org. Chem.  2005,  70:  5133 
  • 2c Zhang L. Malinakova HC. J. Org. Chem.  2007,  72:  1484 
  • 3a Govindachari TR. Chinnasamy P. Rajeswari S. Chandrasekaran S. Premila MS. Natarjan S. Nagarajan K. Pai BR. Heterocycles  1984,  22:  585 
  • 3b Venkov AP. Mollov NM. Synthesis  1982,  216 
  • 4 Phillion DP. Walker DM. J. Org. Chem.  1995,  60:  8417 
  • 5 Parham WE. Bradsher CK. Acc. Chem. Res.  1982,  15:  300 
  • 6a Reich HJ. Green DP. Phillips NH. J. Am. Chem. Soc.  1989,  111:  3444 
  • 6b Reich HJ. Green DP. Phillips NH. J. Am. Chem. Soc.  1991,  113:  1414 
  • 6c Beak P. Musick TJ. Liu C. Cooper T. Gallagher DJ. J. Org Chem.  1993,  58:  7330 
  • 7 Bailey WF. Gagnier RP. Patricia JJ. J. Org. Chem.  1984,  49:  2098 
  • 8 Campbell JB. Dedinas RF. Trumbower-Walsh SA.
    J. Org. Chem.  1996,  61:  6205 
  • 9a Enders D. Braig V. Raabe G. Can. J. Chem.  2001,  79:  1528 
  • 9b

    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).

  • 11 Johnson CD. Acc. Chem. Res.  1993,  26:  476 
  • 12 The stilbene is thought to arise from nucleophilic attack at the benzylic chloride of the acid chloride/imine adduct by another molecule of adduct which has been deprotonated at the a-chlorobenzylic position. Elimination of chloride from the resulting chloro-substituted 1,2-diphenylethane would then afford the stilbene. See: Kobrich G. Angew. Chem., Int. Ed. Engl.  1972,  11:  473 
  • 13a Mehta G. Rao HS. In The Chemistry of Alkanes and Cycloalkanes   Patai S. Rappoport Z. John Wiley and Sons; New York: 1992.  p.583-584  
  • 13b Billington DC. Coupling Reactions Between sp³ Carbon Centers, In Comprehensive Organic Synthesis   Vol. 3:  Trost BM. Pergamon Press; Oxford: 1991.  Chap. 2.1. p.414 
  • 13c Billington DC. Coupling Reactions Between sp³Carbon Centers, In Comprehensive Organic Synthsis   Vol. 3:  Trost BM. Pergamon Press; Oxford: 1991.  Chap. 2.1. p.422 
  • 13d Kwa TL. Tetrahedron  1969,  25:  5771 
  • 14a Fukagawa T. Fujiwara Y. Yokoo K. Taniguchi H. Chem. Lett.  1981,  10:  1771 
  • 14b Yokoo K. Fukagawa T. Yamanaka Y. Taniguchi H. Fujiwara Y. J. Org. Chem.  1984,  49:  3237 
  • 15 Girard P. Namy JL. Kagan HB. J. Am. Chem. Soc.  1980,  102:  2693 
  • 16 Matsumoto H. Inaba S. Rieke RD. J. Org. Chem.  1983,  48:  840 
  • 17a Semmelhack MF. Helquist P. Jones LD. Keller L. Mendelson L. Speltz Ryono L. Gorzynski Smith J. Stauffer RD. J. Am. Chem. Soc.  1981,  103:  6460 
  • 17b Tsou TT. Kochi JK. J. Am. Chem. Soc.  1979,  101:  7547 
  • 18 Chen Y.-H. Knochel P. Angew. Chem. Int. Ed.  2008,  47:  7569 
  • 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.