Conversion of Nucleophilic Halides to Electrophilic Halides: Efficient and Selective Halogenation of Azinones, Amides, and Carbonyl Compounds Using Metal Halide/Lead Tetraacetate

Abstract

AlCl₃/Pb(OAc)₄ and ZnBr₂/Pb(OAc)₄ are efficient electrophilic N- and α-C-halogenating agents. A variety of azinones, amides and carbonyl compounds were chemoselectively and regio­selectively N-, or α-C-halogenated in good to excellent yield using AlCl₃/Pb(OAc)₄ and ZnBr₂/Pb(OAc)₄ in acetonitrile.

Key words

N-halogenation, - α-C-halogenation - electrophilic halogenation - selective halogenation - metal halide/lead tetraacetate

References and Notes

• 1a De Kimpe N. Verhe R. In The Chemistry of α-Haloketones, α-Haloaldehydes and α-Haloimines   Patai S. Rappoport Z. John Wiley; Chichester, UK: 1988.  p.1-119  
• 1b Smith MB. March J. In March’s Advanced Organic Chemistry   5th ed.:  John Wiley and Sons, Inc.; New York: 2001.  p.559-561  
• 1c Smith MB. March J. In March’s Advanced Organic Chemistry   5th ed.:  John Wiley and Sons, Inc.; New York: 2001.  p.1212-1213  
• 1d Smith MB. March J. In March’s Advanced Organic Chemistry   5th ed.:  John Wiley and Sons, Inc.; New York: 2001.  p.1403-1405  
• 2 Larock RC. Comprehensive Organic Transformations   2nd ed.:  VCH Publishers Inc.; New York: 1999.  p.715-719  
• For examples of α-bromo 1,3-dicarbonyl compounds in organic transformations, see:
• 3a Misa AP. Raj K. Bhaduri AP. Synth. Commun.  1999,  29:  3227 
• 3b Coats SJ. Wasserman HH. Tetrahedron Lett.  1995,  36:  7735 
• 3c Endo M. Droghini R. Can. J. Chem.  1988,  66:  1400 
• 3d Hlavka J. Bitha P. Lin Y. Srohmeyer T. J. Heterocycl. Chem.  1985,  22:  1317 
• 4 Fieser M. Fieser LF. Reagents for Organic Synthesis   John Wiley and Sons; New York: 1967.  p.78 
• 5 Barton DRH. Ollis WD. In Comprehensive Organic Chemistry   Vol. 2:  Trost BM. Fleming I. Pergamon Press; Oxford: 1979.  p.1030 
• 6a Kosower EM. Cole WJ. Wu GS. Cardy DE. Meisters G. J. Org. Chem.  1963,  28:  630 
• 6b King LC. Ostrum GK. J. Org. Chem.  1964,  29:  3459 
• 7 Warnhoff EW. Martin DG. Johnson WS. Org. Synth., Coll. Vol. IV   J. Wiley and Sons; New York: 1963.  p.162 
• 8 Brummond KM. Gesenberg KD. Tetrahedron Lett.  1999,  40:  2231 
• 9 Lee JC. Bae YH. Chang SK. Bull. Korean Chem. Soc.  2003,  24:  407 
• 10 Lee JC. Park JY. Yoon SY. Bae YH. Lee SJ. Tetrahedron Lett.  2004,  45:  191 
• 11a Schlama T. Gabriel K. Gouverneur V. Mioskowski C. Angew. Chem., Int. Ed. Engl.  1997,  36:  2342 
• 11b Kajigaeshi S. Kakinami T. Okamoto T. Fujisaki S. Bull. Chem. Soc. Jpn.  1987,  60:  1159 
• 12 Pearson DI. Poper HW. Hargrove WE. Org. Synth., Coll. Vol. V   J. Wiley and Sons; New York: 1973.  p.117 
• 13 Yang D. Yan Y.-L. Lui B. J. Org. Chem.  2002,  67:  7429 
• 14 Poisel H. Schmidt U. Angew. Chem., Int. Ed. Engl.  1976,  15:  294 
• 15 Kolar AJ. Olsen RK. Synthesis  1977,  457 
• 16 Daoust B. Lessard J. Tetrahedron  1999,  55:  3495 
• 17 Miosses B. Danion-Bougot R. Danion D. Synthesis  1994,  1171 
• 18 de Souza SPL. da Silva JFM. de Mattos MCS. Synth. Commun.  2003,  33:  935 
• 19 Freeman JP. Org, Synth. Coll. Vol. VII   John Wiley and Sons; New York: 1993.  p.167 
• 20 Larionov OV. Kozhushkov SI. de Meijere A. Synthesis  2003,  1916 
• 21 Park YD. Kim JJ. Lee SG. Falck JR. Yoon YJ. Synthesis  2005,  1136 
• 22 Marigo M. Kumaragurubaran N. Jorgensen KA. Chem. Eur. J.  2004,  10:  2133 
• 23 Drago RS. Wenz DA. Carlson RJ. J. Am. Chem. Soc.  1962,  84:  1106 
• 24 Bachand C. Driguez H. Paton JM. Touchard D. Lessard J. J. Org. Chem.  1974,  39:  3136 
• 25 Curini M. Epifano F. Marcotullio MC. Rosati O. Tsadjout A. Synlett  2000,  813 
• 26 Luca LD. Giacomelli G. Nieddu G. Synlett  2005,  223 
• 27 Kim JJ. Park YD. Cho SD. Kim HK. Chung HA. Lee SG. Falck JR. Yoon YJ. Tetrahedron Lett.  2004,  45:  8781 
• 28 Muathen HA. Tetrahedron  1996,  52:  8863 
• 29 Bulter RN. Synthetic Reagents   Pizey JS. Ellis Horwood Ltd; New York: 1977.  p.277 
• 30 Kalvoda J. Heusler K. Synthesis  1971,  501 
• 33 Day JC. Govindaraj N. McBain DS. Skell PS. Tanko JM. J. Org. Chem.  1986,  51:  4959 

31

Typical N-Chlorination of Azinones, Amides and Carbonyl Compounds.
Pb(OAc)₄ (2.0 or 4.0 mmol) was dissolved in MeCN (20 mL). AlCl₃ or ZnCl₂ (2.0 or 4.0 mmol) was added to the MeCN solution, and the mixture was stirred for 5 min at r.t. After adding the nitrogen heterocycle (2 mmol) or carbonyl compound (2 mmol) to the above solution, the resulting mixture was refluxed until nitrogen heterocycle or carbonyl compound was disappeared. After evaporating the solvent under reduced pressure, the resulting residue was applied to the top of an open-bed silica gel column (3.0 × 7 cm). The column was eluted with CH₂Cl₂ or CH₂Cl₂-n-hexane (1:1). Fractions containing the product were combined and evaporated under reduced pressure to give monochlorides and/or dichlorides.
Selected Analytical Data.2,4,5-Trichloropyridazin-3(2 H )-one: colorless crystals (CH₂Cl₂); mp 146-147 °C (lit. [21] 146-147 °C). TLC (CH₂Cl₂): R _f = 0.5. IR (KBr): 3100, 1700, 1600, 1580, 1360, 1260, 1180, 1160, 960 cm^-1. ¹H NMR (CDCl₃): δ = 7.76 (s, 1 H) ppm. ¹³C NMR (CDCl₃): δ = 134.8, 137.0, 137.5, 153.8 ppm. Anal. Calcd for C₄HCl₃N₂O: C, 24.09; H, 0.51; N, 14.05. Found: C, 24.10; H, 0.53; N, 14.07.
N -Chloroisoindole-1,3-dione: colorless crystals (CH₂Cl₂); mp 184-185 °C. TLC (CH₂Cl₂): R _f = 0.73. IR (KBr): 3070, 2950, 2880, 1750, 1720, 1620, 1510, 1470, 1360, 1310, 1080, 860 cm^-1. ¹H NMR (CDCl₃): δ = 7.82-7.84 (m, 2 H), 7.89-7.93 (m, 2 H) ppm. ¹³C NMR (CDCl₃): δ = 123.9, 131.0, 134.7, 163.3 ppm. Anal. Calcd for C₈H₄ClNO₂: C, 52.92; H, 2.22; N, 7.71. Found: C, 52.98; H, 2.24; N, 7.79.
N , N -Dichlorotoluene-4-sulfonamide: colorless crystals (CH₂Cl₂); mp 130-131 °C. TLC (CH₂Cl₂): R _f = 0.57. IR (KBr): 3100, 3070, 1860, 1770, 1600, 1470, 1360, 1250, 1100, 910 cm^-1. ¹H NMR (CDCl₃): δ = 7.91-7.95 (m, 2 H), 8.02-8.06 (m, 2 H) ppm. ¹³C NMR (CDCl₃): δ = 125.7, 131.3, 136.1, 162.8 ppm. Anal. Calcd for C₈H₄Br₂N₂O₂: C, 30.03; H, 1.26; N, 8.76. Found: C, 30.11; H, 1.30; N, 8.82.
2-Acetyl-2-chloro-3,4-dihydro-2 H -naphthalen-1-one: colorless crystals (CH₂Cl₂-n-hexane = 1:1); mp 49-50 °C (lit. [21] mp 48-50 °C). TLC (CH₂Cl₂-n-hexane = 1:1): R _f = 0.51. IR (KBr): 2950, 1720, 1680, 1600, 1460, 1420, 1360, 1300, 1240, 1200, 900, 850, 750, 720 cm^-1. ¹H NMR (CDCl₃): δ = 2.42 (s, 3 H), 2.45-2.51 (m, 1 H), 2.90-2.99 (m, 1 H), 3.05-3.08 (m, 1 H), 3.12-3.16 (m, 1 H), 7.41-7.46 (m, 2 H), 7.63-7.69 (m, 1 H), 7.95 (d, 1 H, J = 7.8 Hz) ppm. ¹³C NMR (CDCl₃): δ = 25.0, 26.6, 30.0, 75.9, 127.3, 127.7, 129.2, 129.5, 134.7, 142.9, 189.3, 201.0 ppm. Anal. Calcd for C₁₂H₁₁ClO₂: C, 64.73; H, 4.98. Found: C, 64.75; H, 4.99.
2,2-Dichloro-1-phenylbutane-1,3-dione: colorless crystals (CH₂Cl₂-n-hexane = 1:2); mp 75-76 °C (lit. [21] mp 75-76 °C). TLC (CH₂Cl₂-n-hexane = 1:2): R _f = 0.50. IR (KBr): 3070, 2930, 2880, 1760, 1730, 1710, 1680, 1600, 1580, 1510, 1450, 1360, 1250, 1230, 840, 780, 690, 660, 580 cm^-1. ¹H NMR (CDCl₃): δ = 2.47 (s, 3 H), 7.46-7.54 (m, 2 H), 7.61-7.67 (m, 1 H), 8.06-8.10 (m, 2 H) ppm. ¹³C NMR (CDCl₃): δ = 24.9, 86.5, 128.7, 130.6, 130.9, 134.5, 185.9, 192.2 ppm. Anal. Calcd for C₁₀H₈Cl₂O₂: C, 51.98; H, 3.49. Found: C, 51.99; H, 3.52.
2,2-Dichloroindan-1,3-dione: colorless crystals (CH₂Cl₂-n-hexane = 1:1); mp 125-126 °C. TLC (CH₂Cl₂-n-hexane = 1:1): R _f = 0.63. IR (KBr): 3100, 3060, 2930, 2880, 1780, 1740, 1600, 1260, 1160, 870, 810, 780, 650 cm^-1. ¹H NMR (CDCl₃): δ = 8.07-8.11 (m, 2 H), 8.13-8.17 (m, 2 H) ppm. ¹³C NMR (CDCl₃): δ = 72.8, 125.8, 137.0, 138.1, 186.4 ppm. Anal. Calcd for C₈H₄Cl₂O₂: C, 50.27; H, 1.87. Found: C, 50.29; H, 1.91.

32

Typical N-Bromination of Azinones, Amides and Carbonyl Compounds.
Pb(OAc)₄ (2.0 or 4.0 mmol) was dissolved in MeCN (20 mL). ZnBr₂ (2.0 or 4.0 mmol) was added to the MeCN solution, and the mixture was stirred for 5 min at r.t. The nitrogen heterocycle (2 mmol) or carbonyl compound (2 mmol) was added to the resulting solution. The resulting mixture was stirred at r.t. until nitrogen heterocycle or carbonyl compound disappeared. After evaporating the solvent under reduced pressure, the resulting residue was applied to the top of an open-bed silica gel column (3.0 × 7 cm). The column was eluted with CH₂Cl₂ or CH₂Cl₂-n-hexane (1:1). Fractions containing the product were combined and evaporated under reduced pressure to give monobromides or dibromides. Selected Analytical Data.
2-Bromo-3,4-dichloropyridazin-3(2 H )-one: colorless crystals (CH₂Cl₂); mp 169 °C. IR (KBr): 3100, 1690, 1600, 1460, 1400, 1300, 1260, 1120, 960 cm^-1. ¹H NMR (CDCl₃): δ = 7.50 (s, 1 H) ppm. ¹³C NMR (CDCl₃): δ = 132.3, 136.2, 154.7, 168.0 ppm. Anal. Calcd for C₄HBrCl₂N₂O: C, 19.70; H, 0.41; N, 11.49. Found: C, 19.76; H, 0.43; N, 11.51.
N -Bromoisoindole-1,3-dione: colorless crystals (CH₂Cl₂); mp 199-200 °C (lit. [33] mp 198-202 °C). TLC (CH₂Cl₂): R _f = 0.76. IR (KBr): 3090, 3050, 1775, 1730, 1690, 1610, 1460, 1350, 1290, 1100, 1070, 860, 800, 700 cm^-1. ¹H NMR (CDCl₃): δ = 7.73-7.77 (m, 2 H), 7.88-7.91 (m, 2 H) ppm. ¹³C NMR (CDCl₃): δ = 123.8, 131.9, 134.3, 165.0 ppm. Anal. Calcd for C₈H₄BrNO₂: C, 42.51; H, 1.78; N, 6.20. Found: C, 42.59; H, 1.84; N, 6.27.
2,3-Dibromophthalazine-1,4-dione: colorless crystals (CH₂Cl₂); mp 130-131 °C. TLC (CH₂Cl₂): R _f = 0.57. IR (KBr): 3100, 3070, 1860, 1770, 1600, 1470, 1360, 1250, 1100, 910 cm^-1. ¹H NMR (CDCl₃): δ = 7.91-7.95 (m, 2 H), 8.02-8.06 (m, 2 H) ppm. ¹³C NMR (CDCl₃): δ = 125.7, 131.3, 136.1, 162.8 ppm. Anal. Calcd for C₈H₄Br₂N₂O₂: C, 30.03; H, 1.26; N, 8.76. Found: C, 30.11; H, 1.30; N, 8.86.
2-Bromo-1-phenylbutane-1,3-dione: colorless oil. TLC (CH₂Cl₂): R _f = 0.52. IR (KBr): 3080, 2970, 2940, 1720, 1680, 1600, 1450, 1360, 1300, 1230, 1190, 1000, 760, 690, 550 cm^-1. ¹H NMR (CDCl₃): δ = 2.44 (s, 3 H), 5.67 (s, 1 H), 7.46-7.52 (dd, 2 H, J = 7.87, 7.41 Hz), 7.50-7.65 (m, 1 H), 7.95-7.98 (m, 2 H) ppm. ¹³C NMR (CDCl₃): δ = 27.2, 53.0, 128.6, 129.0, 129.2, 134.5, 190.0, 198.1 ppm. Anal. Calcd for C₁₀H₈BrO₂: C, 49.82; H, 3.76. Found: C, 49.84; H, 3.80.
2,2-Dibromomalonic Acid Diethyl Ester: colorless oil. TLC (CH₂Cl₂-n-hexane = 1:1): R _f = 0.50. IR (KBr): 2980, 2930, 2890, 1760, 1740, 1465, 1445, 1390, 1365, 1290, 1240, 1200 cm^-1. ¹H NMR (CDCl₃): δ = 1.32-1.37 (t, 6 H, J = 7.13 Hz), 4.33-4.41 (q, 4 H, J = 7.13 Hz) ppm. ¹³C NMR (CDCl₃): δ = 13.7, 50.7, 64.7, 163.1 ppm. Anal. Calcd for C₇H₁₀Br₂O₄: C, 26.44; H, 3.17. Found: C, 26.50; H, 3.20.