Daniel Morton Emory University The Hofmann Löffler Freytag HLF Reaction Wikipedia page httpsenwikipediaorgwikiHofmannL ID: 752513
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Slide1
The Hofmann-Löffler-Freytag Reaction
Daniel MortonEmory UniversitySlide2
The Hofmann-Löffler-Freytag (HLF) Reaction
Wikipedia page:
https://en.wikipedia.org/wiki/Hofmann%E2%80%93L%C3%
B6ffler_reaction
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:Slide3
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.Slide4
Mechanistic Investigations of the HLF Reaction
Corey, E. J.; Hertler, W. R. (1960). J. Am. Chem. Soc
. 82 (7): 1657–1668.
Stereochemistry:
Isotope Effect: KH/KD = 3.42 - 3.54Selectivity of Hydrogen Transfer:Single product
Determination of Intermediates: Slide5
Generally Accepted Mechanism of the HLF Reaction
Initiation
Propagation
WorkupSlide6
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. Slide7
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. Slide8
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 oC) or by irradiation with visible (Not UV) light. Slide9
Applications of the Classical HLF Reaction
Corey, E. J.; Hertler, W. R., J. Am. Chem. Soc.,
1958,
80
, 2903.Slide10
Applications of the Classical HLF Reaction
Hora
, J.;
Sorm
, F. (1968). Collect. Czech. Chem. Commun. 33: 2059. 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. Slide11
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. Slide12
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 = NO2 (63%)EWG = CN (64%)EWG = P(O)(OEt)2 (99%)
EWG = NO
2 R = CH3(4
3%)EWG = NO
2 R = CO2Me (65%)
EWG = P(O)(OEt)
2 R = CH2OAc(90%)Slide13
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. Slide14
HLF Variant for the synthesis of 1,3-diols: Pygmol
Chen, K.; Baran, P. S. Nature, 2009
,
459
, 824.