A Convenient Method for in situ Generation of I₂ Using CuSO₄/NaI and Its Applications to the Deprotection of Acetals, Etherifications and ­Iodolactonizations

Abstract

A convenient method for the in situ generation of I₂ using CuSO₄/NaI has been developed. The applications of this method to the deprotection of acetals, etherifications and iodolactonizations have been demonstrated. The use of toxic and corrosive molecular iodine is avoided.

Key words

acetals - chemoselectivity - ethers - lactones - iodine

References and Notes

• 1a Greene TW. Wuts PGM. Protective Groups in Organic Synthesis   3rd ed.:  John Wiley and Sons, Inc; New York: 1999. 
• 1b Hanson JR. Protecting Groups in Organic Synthesis   1st ed.:  Blackwell Science, Inc; Malden, MA: 1999. 
• 1c Kocienski PJ. Protecting Groups   1st ed.:  Georg Thieme Verlag; Stuttgart: 1994. 
• 2a p-TsOH/acetone: Colvin EW. Raphael RA. Roberts JS. J. Chem. Soc., Chem. Commun.  1971,  858 
• 2b 50% Trifluoroacetic acid in CHCl₃-H₂O: Ellison RA. Lukenbach ER. Chiu C.-W. Tetrahedron Lett.  1975,  499 
• 2c LiBF₄: Lipshutz BH. Harvey DF. Synth. Commun.  1982,  12:  267 
• 2d Amberlyst-15/aq acetone: Coppola GM. Synthesis  1984,  1021 
• 2e aq DMSO: Kametani T. Kondoh H. Honda T. Ishizone H. Suzuki Y. Mori W. Chem. Lett.  1989,  901 
• 2f Bi(NO₃)₃·5H₂O: Eash KJ. Pulia MS. Wieland LC. Mohan RS. J. Org. Chem.  2000,  65:  8399 
• 3a TiCl₄: Balme G. Goré J. J. Org. Chem.  1983,  48:  3336 
• 3b FeCl₃·6H₂O on silica gel: Kim KS. Song YH. Lee BH. Hahn CS. J. Org. Chem.  1986,  51:  404 
• 3c Ph₃P/CBr₄: Johnstone C. Kerr W. Scott J. Chem. Commun.  1996,  341 
• 3d CeCl₃: Marcantoni E. Nobili F. J. Org. Chem.  1997,  62:  4183 
• 3e FeCl₃·6H₂O: Sen SE. Roach SL. Boggs JK. Ewing GJ. Magrath J. J. Org. Chem.  1997,  62:  6684 
• 3f TMSN(SO₂F)₂: Kaur G. Trehan A. Trehan S. J. Org. Chem.  1998,  63:  2365 
• 3g Ceric ammonium nitrate: Markó IE. Ates A. Gautier A. Leroy B. Plancher J.-M. Quesnel Y. Vanherck J.-C. Angew. Chem. Int. Ed.  1999,  38:  3207 
• 3h Bi(OTf)₃·4H₂O: Carrigan MD. Sarapa D. Smith RC. Wieland LC. Mohan RS. J. Org. Chem.  2002,  67:  1027 
• 3i HClO₄/silica gel: Agarwal A. Vankar YD. Carbohydrate Res.  2005,  340:  1661 
• 4 Sun J. Dong Y. Cao L. Wang X. Wang S. Hu Y. J. Org. Chem.  2004,  69:  8932 
• 7a Swenton JS. Carpenter K. Chen Y. Kerns ML. Morrow GW. J. Org. Chem.  1993,  58:  3308 
• 7b

  The ¹³C NMR spectrum of the product (entry 7, Table [1] ) has not been previously reported and is given here. ¹³C NMR (CDCl₃): δ = -4.5, 18.1, 25.5, 120.4, 130.3, 131.8, 161.4, 190.7.

• Iodolactonizations using I₂ generated in situ have been previously reported. For examples, see:
• 8a NaI/MCPBA: Srebnik M. Mechoulam R. J. Chem. Soc., Chem. Commun.  1984,  1070 
• 8b Sodium persulfate/KI: Royer AC. Mebane RC. Swafford AM. Synlett  1993,  899 
• 8c FeCl₃/NaI: Chavan SC. Sharma AK. Tetrahedron Lett.  2001,  42:  4923 
• 8d H₂O₂/NaI: Higgs DE. Nelen MI. Detty MR. Org. Lett.  2001,  3:  349 
• 8e Oxone/NaI: Curini M. Epifano F. Marcotullio MC. Montanari F. Synlett  2004,  368 
• 11 Molander GA. Christina R. J. Org. Chem.  1997,  62:  7418 

5

In the deprotection of acetals using molecular I₂ in acetone (ref. 4), the formation of iodoacetone or disappearance of I₂ color was not reported.

6

Typical Procedure for Acetal Deprotection.
A solution of vanillin acetate dimethyl acetal (0.424 g, 1.76 mmol), and NaI (0.159 g, 1.06 mmol, 0.6 equiv) in dry acetone (9.0 mL) was stirred at r.t. under N₂ as anhyd CuSO₄ (0.169 g, 1.06 mmol, 0.6 equiv) was added. The reaction progress was followed by ¹H NMR spectroscopy. After 3 h 25 min, the mixture was suction filtered using a fritted glass funnel and the solids were washed with acetone (5 mL). Then, H₂O (25 mL) was added to the filtrate and most of the acetone was removed on a rotary evaporator. The residue was then extracted with Et₂O (2 × 20 mL) and the organic layer was then washed with aq 10% Na₂S₂O₃ (10 mL), sat. NaCl (10 mL) and dried (Na₂SO₄). The organic layer was concentrated on a rotary evaporator to yield 0.268 g (78%) of vanillin acetate as a white solid that was found to be at least 98% pure.

9

Although solid copper waste is produced in this method, the solids are collected by suction filtration and hence easily contained. No toxic aqueous waste stream is generated.

10

Typical Procedure for Iodolactonization.
5-Hexenoic acid (0.140 g, 1.23 mmol) was stirred in H₂O (17 mL) at r.t. as solid NaHCO₃ (0.206 g, 2.46 mmol, 2 equiv), NaI (0.731 g, 4.91 mmol, 4.0 equiv) and anhyd CuSO₄ (0.769 g, 4.91 mmol, 4 equiv) were added sequentially. After 40 min, the mixture was suction filtered. Then, aq 10% Na₂S₂O₃ (25 mL) was added to the filtrate, which was then extracted with Et₂O (3 × 10 mL). The combined organic layers were washed with sat. NaCl (25 mL) and dried (Na₂SO₄). The solvent was removed on a rotary evaporator to yield 0.248 g (84%) of the product as a pale yellow liquid that was determined to be >96% pure by ¹H NMR and ¹³C NMR analysis.