1. The Hofmann-Löffler-Freytag Reaction
Daniel Morton
Emory University

2. The Hofmann-Löffler-Freytag (HLF) Reaction
General Reaction:
Initial Discovery:
First Application:
The Hofmann–Löffler reaction (also referred to as Hofmann–Löffler–Freytag reaction is an organic reaction in which a cyclic amine (pyrrolidine or, in some cases, piperidine) is generated by thermal or photochemical decomposition of N-halogenated amine in the presence of a strong acid (typically concentrated sulfuric acid or concentrated TFA). The HLF reaction proceeds via an intramolecular 1,5-hydrogen atom transfer to a nitrogen-centered radical and is an early example of a remote intramolecular free radical C–H functionalization.
In the late 1870’s A. W. Hofmann performed a series of experiments designed to determine the then unknown structure of piperidine. In the course of these studies a series of N-haloamines and N-haloamides was synthesized and Hofmann investigated the reaction of these species under acidic and basic conditions. He reported that the treatment of these molecules with hot sulfuric acid followed by basic workup furnished the corresponding tertiary amines. While this was an interesting result the power of this reaction was unrecognized for nearly 25 years.
In 1909 Löffler and Freytag extended the scope of this transformation and set the scene for it to become a general and straightforward method for the formation of pyrrolidines by demonstrating that the reaction was possible with simple secondary amines, showcased by the synthesis of nicotine.
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.

3. Mechanistic Investigations of the HLF Reaction
Although the HLF reaction was initially discovered in the 1880’s, it was not until the late 1950’s that the mechanistic details of this reaction were understood. Two groups played a key role in these investigations.
Wawzonek and Thelan performed investigated the nature of this reaction showing that the reaction proceeded either when performed under irradiation with UV light in the presence of chlorine, or in the dark in the presence of the radical initiator hydrogen peroxide. Based on this evidence they proposed that the reaction proceeds via a radical chain reaction pathway.
Based upon their investigations they made further predictions about the nature of the reaction. They proposed that the first step is protonation of the amine by the acid, followed by homolytic cleavage (promoted by light or a suitable initiator), to afford the amminium and chloride free radicals. The amminium radical abstracts a sterically available hydrogen atom, producing an alkyl radical that in turn abstracts a chlorine atom from another N-chloroammonium ion to form an alkyl chloride and a new amminium radical. Upon basic workup nucleophillic cyclization occurs to form the tertiary amine.
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.

4. Mechanistic Investigations of the HLF Reaction
Stereochemistry:
Selectivity of Hydrogen Transfer:
Single product
Isotope Effect: KH/KD =
Determination of Intermediates:
In the 1950’s the Corey group carried out a detailed and extensive mechanistic investigation of the HLF reaction, with a particular focus on stereochemistry, hydrogen isotope effect, initiation, catalysis, intermediates and selectivity of hydrogen transfer.
Using the deuterated amine Corey et al were able to explore the whether the replacement of hydrogen in the cyclization reaction proceeded with retention, inversion or equilibration of configuration. The product was found to be optically inactive, providing strong evidence that the intermediate species possessed an sp2 hybridized delta-carbon.
Using the deuterated amine allowed another important set of experiments to be carried out, enabling the determination of the hydrogen isotope effect. Analysis of the product mixture gave a value of 0.78 atoms of deuterium per molecule, corresponding to an isotope effect of KH/KD = Verification of this value through comparison of the intensities of stretching absorptions in IR gave a value in good agreement (3.42). These values suggest that the breaking of the C–H bond proceeds to a considerable extent in the transition state.
Building from the proposed mechanism Corey et al were able to isolate the intermediate 4-chlorodibutylamine from the decomposition of dibutylchloroamine in H2SO4. Treatment of the delta-chloroamine with base furnished the cyclized product and a chloride ion.
The investigations then turned to exploring the selectivity of the hydrogen transfer process. Systems were chosen with three perspectives in mind a) relative migration tendencies of primary, secondary and tertiary C–H bonds, b) relative rates of 1,5- and 1,6-hydrogen rearrangements and c) facility of hydrogen rearrangements in cyclic systems of restricted geometry.
In the first reaction with competing primary and secondary C–H bonds, only the product from secondary insertion was observed, suggesting the radical attach has a strong preference for the secondary over the primary C–H bond.
The next reaction looked at primary versus tertiary. While there was rapid disappearance of the starting material, none of the cyclized system was observed. The results suggested that there is a high selectivity for the tertiary C–H bond, but the intermediate tertiary chloro compound was rapidly decomposed. A similar result was seen in a reaction of secondary versus tertiary C–H bonds, suggesting a strong preference for the tertiary CH bonds.
In a competition experiment looking at the relative ease of the 1,5- and 1,6-hydrogen transfer reactions, a 9:1 mixture of the 1,5-hydrogen transfer product was observed, showing good selectivity, though highlighting that appreciable amounts of the 6-membered ring can be formed.
When cyclic and acyclic amines were subjected to the conditions the cyclic systems were observed to be significantly slower, suggesting that the substrates prevailing geometries were unfavorable for this reaction.
Corey, E. J.; Hertler, W. R. (1960). J. Am. Chem. Soc. 82 (7): 1657–1668.

5. Generally Accepted Mechanism of the HLF Reaction
Initiation
Workup
It is generally accepted that the first step in the HLF reaction conducted in acidic medium is the protonation of the N-halogenated amine. In the case of either thermal or chemical generation of the radical the protonated ammonium salt undergoes homolytic cleavage of the N-X bond to generate the the N-centered radical. However, it has been argued that the UV-light-catalyzed initiation involves the free form of the N-haloamine followed by a rapid protonation of the newly generated neutral nitrogen radical. This was proposed by Corey et al by studying the different absorption energy profiles of the different amine forms.
Intramolecular 1,5-hydrogen abstraction is proposed to proceed via the outlined 6-membered transition state, explaining the observed preference for formation of the 5-membered heterocycles. The carbon centered radical then abstracts a halogen from a second molecule of the ammonium salt, propagating the radical chain. Upon treatment of the delta-halogenated amine with base during the workup nucleophillic cyclization affords the observed heterocycle.
Propagation

6. Modifications of the HLF Reaction
Under basic or neutral conditions
One of the key flaws of the HLF reaction were the harsh acidic conditions required in the first step for the protonation of the N-haloamine. In many cases this significantly restricted the substrate scope with respect to functional group tolerance and structure. A number of groups explored solutions to this limitation.
A key observation made by Kimura and Ban in the 1970’s was that incorporation of a nitrogen atom adjacent to the point of H-abstraction significantly stabilized the resulting radical species, permitting this reaction to take place under mildly basic conditions. In their reports they state the critical choice of triethylamine as the base in this reaction, which effectively neutralizes the HCl generated by the cyclization process.
The power of this approach was showcased in the synthesis of the natural product dihydrodeoxyepiallocernuine.
Ban, Y.; Kimura, M.; Oishi, T. (1976). Chem. Pharm. Bull. 24 (7): 1490–1496.
Kimura, M.; Ban, Y. (1976). Synthesis 1976 (3): 201–202.

7. Modifications of the HLF Reaction
Amides in place of the amines
It was found that photolysis of N-haloamides proceeds effectively under neutral conditions in generally very good yield.
A powerful example of this was describe by Baldwin et al, rapidly constructing the core skeleton of the alkaloid gelsemicine.
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.

8. Modifications of the HLF Reaction
The Suárez modification:
EWG = NO2, 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.
Possibly the most important variation of the HLF reaction was first reported by Suárez et al in Initially reporting a process using neutral conditions for the HLF reaction of N-nitroamides, the reaction was explored and optimized, expanding the substrate scope so that this transformation was effective for N-cyanamides, N-phosphoramidates and carbamates.
All of these species react with hypervalent iodine agents in the presence of molecular iodine, generating a nitrogen centered radical via homolytic fragmentation of the iodoamide intermediate. This then proceeds via the established pathway to the heterocycles.
There are a number of advantages to this strategy.
(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.

9. Applications of the Classical HLF Reaction
This report from Corey built upon their mechanistic work to develop a rapid entry into the steroidal alkaloid derivative dihydroconessine.
Corey, E. J.; Hertler, W. R., J. Am. Chem. Soc., 1958, 80, 2903.

10. Applications of the Classical HLF Reaction
In the 1970’s the groups of Hora and Van De Woude expanded on this chemistry in the preparation of a range of conessine steroidal alkaloid derivatives using the classical HLF reaction conditions with a strong acid.
It was proposed that the ease and efficiency of this reaction was due to the nature of the steroidal substrate. Steroids are a privileged molecular scaffold, both in terms of therapeutic activity and development of new reactions. Many novel transformations have used steroids as an effective test substrate. In this case the rigid backbond of the C and D rings bring the reactive groups into close proximity and an effective six-membered ring transition state.
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.

11. Applications of the Suárez Modification of the HLF Reaction
The Suárez modification, capable of achieving the reaction under much milder conditions, has facilitated the application of this technology to a broad scope of substrate, including more functionalized molecules.
In the top example, reported by Suárez in 1989, is an example of the reaction of a series of medium-sized lactams, where the amidyl radical undergoes transannular hydrogen abstraction to form the bicyclic systems.
In 2003 Suárez et al demonstrated that the chemistry was mild and tolerant enough to be effective with sugar derivatives, effecting a formal N-glycosidation 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.

12. Applications of the Suárez Modification of the HLF Reaction
EWG = NO2 (63%)
EWG = CN (64%)
EWG = P(O)(OEt)2 (99%)
EWG = NO2 R = CH3(43%)
EWG = NO2 R = CO2Me (65%)
EWG = P(O)(OEt)2 R = CH2OAc(90%)
As previously mentioned, steroids and steroidal derivatives have long been used as testing grounds for reaction development. Using the modified reaction conditions Suárez et al were able to rapidly access a number of steroid and triterpene derivatives. Interestingly the phosphoramidate-initiated functionalizations were shown to consistently proceed with greater efficiency.
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.

13. HLF Variant for the synthesis of 1,3-diols
In 2008 Baran et al reported a novel HLF variant. Employing a novel electron withdrawing group on the amide, an effective and general method for the synthesis of 1,3-diols was developed, starting from simple alcohol starting materials.
Baran, P. S.; Chen, K.; Richter, J. M. (2008). J. Am. Chem. Soc. 130 (23): 7247–7249.

14. HLF Variant for the synthesis of 1,3-diols: Pygmol
Baran et al demonstrated the power of the new HLF variant as part of their concise total synthesis of pygmol using C–H functionalization logic.
Chen, K.; Baran, P. S. Nature, 2009, 459, 824.