Amination of Carbon-Centered Radical

Despite the fact that nitrosation of cyclohexane is a classical textbook example of an industrial radical reaction [49], only a few procedures for the amination of carbon-centered radicals have been reported. However, some valuable radical alternatives to classical amination processes have been developed and will be described here. 

Radical reactions are widely used for carbon-carbon bond formations. This has led to highly efficient novel synthetic methods that can be used in natural product synthesis as well as preparation of fine chemicals. Many of these processes involve a reductive final step (see for instance Volume 1, Chapter 1.3). Alternative methods that allow functionalization of carbon-centered radicals are highly desired. In this chapter, we will focus on oxygenation and amination reactions. 

In 2010, Nicholas and co-workers studied the enantioselective ben lic amination reactions.As shown in Table 1.11, they tested different kinds of ligands including (S)-histidine, (5)-proline, diimine ligands, and chiral phenanthroline. Although the corresponding product can be prepared with high yields, the enantioselectivity is low. The preliminary results from the mechanistic studies support a stepwise C—H bond insertion process, most likely through the intermediacy of carbon-centered radicals. Subsequently, they expanded this reaction to an intramolecular version with up to 18% ee. ... 

Numerous reports published in recent years have focused on carbon-centered radicals derived from compounds with selected substitution patterns such as alkanes [40,43,47], halogenated alkanes [43,48,49,51-57], alkenes [19], benzene derivatives [43,47], ethers [51,58], aldehydes [48], amines [10,59], amino acids [23,60-67] etc. Particularly significant advances have been made in the theoretical treatment of radicals occurring in polymer chemistry and biological chemistry. The stabilization of radicals in all of these compounds is due to the interaction of the molecular orbital carrying the unpaired electron with energetically and spatially adjacent molecular orbitals, and four typical scenarios appear to cover all known cases [20]. 

This mechanism is of importance in radical induced amino acid damage catalyzed by copper ions. The study of the decomposition of transients with a metal-carbon -bond containing two potential leaving groups (both an amine and a carboxylate group) at the p position of the carbon centered radical is of special interest. It was reported that the intermediate formed with the amino acid 2-methylalanine with cupric ions decomposes via p-carboxyl elimination whereas the intermediate formed with cuprous ions decomposes via p-amine elimination (102). 

In the case of amines, protonation that withdraws electron density from the center of reaction lowers the rate of reaction by a factor of 30 (Das and von Sonntag 1986). Besides H-abstraction from carbon [reactions (18) and (21)], the formation of N-centered radical cations is observed [reactions (19)/(22) and (20) for amino acids see, e.g Bonifacic et al. 1998 Hobel and von Sonntag 1998]. Reaction (20) is also an H-abstraction reaction. The ET reaction (19)/(22) may proceed via a (bona-fide, very short-lived) adduct (Chap. 7). 

Nitro compounds may add to carbon-centered radicals and thus also with the majority of the DNA radicals (Chap. 6.3 only the very strongly reducing radicals such as eaq and C02 reduce the nitro sensitizers to (unstable) hydroxyl-amines McClelland et al. 1984). Originally, the nitro compounds and 02 have just been taken as oxidants irrespective of their mode of action, especially as the efficiency of the sensitizers correlates with their reduction potential (Adams and Cooke 1969 Tallentire et al. 1972 Simic and Powers 1974 Adams et al. 1976a, 1981). This concept is expressed in relationship (88), where C is the sensitizer concentration required to achieve a constant sensitizing response (e.g. an enhancement ratio of 1.6) and E7 the one-electron reduction potential of the sensitizer at pH 7. 

As a reductive condition, treatment of a,a,a-trichloroacetate (233) with a Cu1+-tris(pyridylmethyl)amine complex generates macrocyclic polyether (234) through initial SET from Cu1+ to trichloride, generation of a,a-dichloroacetate radical, 18-endo-trig ring closure, and abstraction of a chlorine atom from the a,a,a-trichloroacetate (233) by the formed carbon-centered radical as shown in eq. 3.92 [239]. 

The pioneering work of Conant showed that the one-electron reduction of pyridinium ion by low-valent vanadium produces the corresponding carbon radical, which dimerizes to give a homocoupling product. Saveant studied the electrochemical reduction of stable iminium salts, and observed two reduction waves in the polarograms (Scheme 5.27). The first wave corresponds to the one-electron reduction process for which dimerization occurs. This process presumably involves formation of the carbon centered radical. The second wave is concerned with the formation of the amine by two-electron reduction. Wayner performed extensive work on oxidation and reduction potentials of carbon radicals.A modulated... 

Radical oxygenation can be performed by reaction with nitroxides to give alkoxyl-amines that are easily reduced to the corresponding alcohols by classical methods. The high reactivity of the nitroxides toward carbon-centered radicals make it a valuable alternative to oxygen for hydroxylation processes. 

Radical methods are of central importance in organic synthesis [1], These reactions are performed under mild and neutral conditions, which usually avoids competing ionic side reactions. Carbon-centered radicals are compatible with a range of functional groups (e.g. aliphatic alcohols, amines, ketones, esters) and also show high chemoselectivity under carefully controlled reaction conditions. Furthermore, reactions involving loss of stereochemistry at the non-radical center are not problematic, and hence radical methods are emerging as a powerful synthetic tool in the field of carbohydrate chemistry. 

In the mid-1980s, the first technique that relies on the reversible termination of radicals with a stable free radical was developed in the group of E. Rizzardo at CSIRO in Australia. Rizzardo and co-workers found that nitroxide-stable free radicals were able to add to carbon-centered radicals to form alkoxy amines (9). In certain cases these alkoxy amines are thermally unstable, so that they enter into an equilibrium between (transient) carbon-centered radical and (persistent) nitroxide radical on one side, and alkoxy amine on the other side. TEMPO was initially the most frequently used nitroxide in conjunction with the polymerization of styrene and its derivatives. The TEMPO-polystyrene adduct requires temperatures of 120° C or above in order to establish an equilibrium at which polymerization takes place. Around the mid-1990s Georges and co-workers focused on the TEMPO-mediated pol5unerization of styrene (10), and developed various strategies to overcome intrinsic weaknesses of the system. They used camphor sulfonic acid to enhance the rate of polymerization (11). This rate enhancement was later elucidated to be due to the destruction of excess nitroxide that builds up during the polymerization. 

Generation of free radicals from a conventional free-radical initiator (eg, azo compound or peroxide), addition of one or a few monomer units, followed by trapping of the carbon-centered radical by the nitroxide compound (1). The trapping reaction produces an alkoxy amine, which contains a thermally labile C—0 bond (44). 

The scope of the reaction is quite broad, and a number of functional groups are tolerated in the reaction. Radicals generated at the carbonyl of an amide or a to an alcohol, ether (45) or amine can be utilized in the Minisci reaction. Minisci, later, showed homolysis of sugar-derived alkyl iodides 46 under thermal conditions to give carbon-centered radicals. These radicals undergo HAS to quinoline derivatives 47 and other heteroaromatics in good yields. Cowden showed that decarboxylation of commercially available a-amino acids 48 can form a carbon-centered radical for use in the Minisci reaction. ... 

The hydrohydrazination represented a general solution for the amination of alkenes, but the protected hydrazines obtained are sometimes difficult to transform to the free amines. At this point, we turned to sulfonyl azides as nitrogen sources, based on then-capacity to react both with enolates and carbon-centered radicals. Mechanistic investigations of the hydrohydrazination reaction had suggested a radical character for the formed organocobalt intermediate. " We were pleased to see that the Cobalt-catalyst 4 was able to promote the hydroazidation of 4-phenylbut-l-ene (3) with ethanesulfonyl azide (7), giving the product derived from the formal Markovnikov addition of hydrazoic acid onto the C-C double bond exclusively, albeit in moderate yields (50%). 

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