Organic Pedagogical Electronic Network The Hofmann-Löffler-Freytag Reaction Daniel Morton Emory University

The Hofmann-Löffler-Freytag (HLF) Reaction Wikipedia page: Initial Discovery: (a) Hofmann, A. W. (1879). Ber. Dtsch. Chem. Ges. 12 (1): 984–990 (b) Hofmann, A. W. (1881). Ber. Dtsch. Chem. Ges. 14 (2): 2725–2736. (c) Hofmann, A. W. (1883). Ber. Dtsch. Chem. Ges. 16 (1): 558–560. (d) Hofmann, A. W. (1885). Ber. Dtsch. Chem. Ges. 18 (1): 5–23. (e) Hofmann, A. W. (1885). Ber. Dtsch. Chem. Ges. 18 (1): 109–131. First Application: (a) Löffler, K.; Freytag, C. (1909). Ber. Dtsch. Chem. Ges. 42 (3): 3427–3431. (b) Löffler, K.; Kober, S. (1909). Ber. Dtsch. Chem. Ges. 42 (3): 3431–3438. General Reaction: Initial Discovery:First Application:

Mechanistic Investigations of the HLF Reaction Wawzonek, S.; Thelan, P. J. (1950). J. Am. Chem. Soc. 72 (5): 2118–2120. Wawzonek, S.; Thelan, M. F., Jr; Thelan, P. J. (1951). J. Am. Chem. Soc. 73 (6): Wawzonek, S.; Culbertson, T. P. (1959). J. Am. Chem. Soc. 81 (13): 3367–3369.

Mechanistic Investigations of the HLF Reaction Corey, E. J.; Hertler, W. R. (1960). J. Am. Chem. Soc. 82 (7): 1657–1668. Stereochemistry: Isotope Effect: K H /K D = Selectivity of Hydrogen Transfer: Single product Determination of Intermediates:

Generally Accepted Mechanism of the HLF Reaction Initiation Propagation Workup

Modifications of the HLF Reaction Ban, Y.; Kimura, M.; Oishi, T. (1976). Chem. Pharm. Bull. 24 (7): 1490–1496. Kimura, M.; Ban, Y. (1976). Synthesis 1976 (3): 201–202.

Modifications of the HLF Reaction Chow, Y. L.; Mojelsky, T. W.; Magdzinski, L. J.; Tichy, M. (1985). Can. J. Chem. 63 (8): 2197–2202. Baldwin, S. W.; Doll, T. J. (1979). Tetrahedron Lett. 20 (35): 3275–3278.

Modifications of the HLF Reaction (a) Hernández, R.; Rivera, A.; Salazar, J. A.; Suárez, E. (1980). J. Chem. Soc., Chem. Commun. (20): 958–959. (b) De Armas, P.; Francisco, C. G.; Hernández, R.; Salazar, J. A.; Suárez, E. (1988). J. Chem. Soc., Perkin Trans. 1 (12): 3255–3265. (c) Carrau, R.; Hernández, R.; Suárez, E.; Betancor, C. (1987). J. Chem. Soc., Perkin Trans. 1: 937–943. (d) Francisco, C. G.; Herrera,A. J.; Suárez, E. (2003). J. Org. Chem. 68 (3): 1012–1017. (e) Betancor, C.; Concepción, J. I.; Hernández, R.; Salazar, J. A.; Suárez, E. (1983). J. Org. Chem. 48 (23): 4430–4432. (f) De Armas, P.; Carrau, R.; Concepción, J.I.; Francisco, C.G.; Hernández, R.; Suárez, E. (1985). Tet. Lett. 26 (20): 2493–2496. The Suárez modification: EWG = NO 2, CN, P(O)(OR) 2, CBz, Boc Reaction can be performed under very mild neutral conditions Compatible with many functional and protecting groups Unstable iodoamine intermediates are generated in-situ Iodoamine homolysis proceeds thermally at low temperature (20-40 o C) or by irradiation with visible (Not UV) light.

Applications of the Classical HLF Reaction Corey, E. J.; Hertler, W. R., J. Am. Chem. Soc., 1958, 80, 2903.

Applications of the Classical HLF Reaction Hora, J.; Sorm, F. (1968). Collect. Czech. Chem. Commun. 33: Van De Woude, G.; van Hove, L. (1973). Bull. Soc. Chim. Belg. 82 (1–2): 49–62. Van De Woude, G.; van Hove, L. (1975). Bull. Soc. Chim. Belg. 84 (10): 911–922. Van De Woude, G.; Biesemans, M.; van Hove, L. (1980). Bull. Soc. Chim. Belg. 89 (11): 993–1000.

Applications of the Suárez Modification of the HLF Reaction Dorta, R. L.; Francisco, C. G.; Suárez, E. (1989). Chem. Commun. (16): 1168–1169. Francisco, C. G.; Herrera,A. J.; Suárez, E. (2003). J. Org. Chem. 68 (3): 1012–1017.

Applications of the Suárez Modification of the HLF Reaction De Armas, P.; Francisco, C. G.; Hernández, R.; Salazar, J. A.; Suárez, E. (1988). J. Chem. Soc., Perkin Trans. 1 (12): 3255–3265. Carrau, R.; Hernández, R.; Suárez, E.; Betancor, C. (1987). J. Chem. Soc., Perkin Trans. 1: 937–943. Betancor, C.; Concepción, J. I.; Hernández, R.; Salazar, J. A.; Suárez, E. (1983). J. Org. Chem. 48 (23): 4430–4432. De Armas, P.; Carrau, R.; Concepción, J.I.; Francisco, C.G.; Hernández, R.; Suárez, E. (1985). Tet. Lett. 26 (20): 2493–2496. EWG = NO 2 (63%) EWG = CN (64%) EWG = P(O)(OEt) 2 (99%) EWG = NO 2 R = CH 3 (43%) EWG = NO 2 R = CO 2 Me (65%) EWG = P(O)(OEt) 2 R = CH 2 OAc(90%)

HLF Variant for the synthesis of 1,3-diols Baran, P. S.; Chen, K.; Richter, J. M. (2008). J. Am. Chem. Soc. 130 (23): 7247–7249.

HLF Variant for the synthesis of 1,3-diols: Pygmol Chen, K.; Baran, P. S. Nature, 2009, 459, 824.

Problems Highlight the C–H bonds you expect to react in the following substrates: Predict the products of the following reactions: