Barton reaction radical addition reactions

A radical approach to asymmetnc iildol synthesis, which is based on the radical addition of a chiral hydroxyalkyl radical equivalent to a tutroalkene, has been reported, as shown in Eq 4 93 The radical precursor is prepared from the corresponding carboxyhc acid by the Barton reaction, which has been used for synthesis of new fi-lactams ... 

The involvement of an intramolecular hydrogen abstraction in the Barton reaction is not necessarily limited to those molecules with rigid stereochemistry. In fact, simple aliphatic nitrites undergo the Barton reaction with equal ease. Thus, the principal product obtained from the photolysis of ra-octyl nitrite20 in benzene solution is the dimer of 4-nitroso-l-octanol however, photolysis of n-octyl nitrite in n-heptane20 produced a mixture of 7/-nitroso heptanes in addition to 4-nitroso-l-octanol in the ratio l 4.5,f respectively. The formation of y-nitroso heptane obviously results from an attack of the intermediate alkoxy radical on the solvent molecule. The intermediate alkyl radical then collapses, according to eq. 2. For the sake of convenience we have indi-... 

Thioethers have also been prepared on cross-linked polystyrene by radical addition of thiols to support-bound alkenes and by reaction of support-bound carbon radicals (generated by addition of carbon radicals to resin-bound acrylates) with esters of l-hydroxy-l,2-dihydro-2-pyridinethione ( Barton esters Entry 6, Table 8.5). Additional methods include the reaction of metallated supports with symmetric disulfides (Entries 7-9, Table 8.5) and the alkylation of polystyrene-bound, a-lithiated thioani-sole [65],... 

This "thiophilic" mode of reaction fits well with the other ionic and radical thiophilic additions on a thiocarbonyl group (see [120], and the Barton-McCombie radical thiophilic addition [227] previously discussed in Sections 4.2.2 and 3.2). With thioaldehydes, both C-C and C-S bonds were formed, as in the following case in which 0-pinene was used to trap thiobenzaldehyde [514] ... 

The basic transformation that underlies the Barton method is outlined in Scheme 45, steps 1 and 2.152 Thermolysis in refluxing toluene or photolysis with a sunlamp rapidly converts a thiohydroxamate ester (32) to the decarboxylated pyridyl sulfide (33). This pyridyl sulfide is formed by addition of an alkyl radical R to the thiohydroxamate (32) followed by fragmentation of (34) as indicated. In the planning of addition reactions by the Barton method, it is usually assumed that the addition step 1 is rate limiting. However, there is now evidence that step 1 may sometimes be reversible and step 2 may be rate limiting.153... 

Sequences in which addition precedes cyclization are not as straightforward to conduct as the reverse however, they are very important because a net annulation results (that is, a new ring is formed by the union of two acyclic precursors in one experimental step). The intermediate radical is differentiated from the other radicals provided that the cyclization reaction is rapid, but it can be difficult to differentiate the initial radical from the final radical. As illustrated in Scheme 57, this is particularly true in the tin hydride method because many different types of radicals react with tin hydride at similar rates. Reaction of (69) under standard radical addition conditions produces (70), which results from a sequence of addition/cy-clization/addition.233 That the last C—C bond is formed actually results from a lack of selectivity the initial and final radicals are not differentiated and they must undergo the same reaction. Of course, this lack of selectivity is of no consequence if the product contains the desired skeleton and the needed functionality for subsequent transformations. Such sequences are very useful for forming three carbon-carbon bonds, and they can also be conducted by Barton s thiohydroxamate method.234 Structural modifications are required to differentiate the initial and final radicals, and, as illustrated by the conversion of (71) to (72), phenyl groups can provide the needed differentiation (probably by retarding the rate of addition more than they retard the rate of hydrogen abstraction). Clive has demonstrated that phenyl-substituted vinyl radicals also provide the needed selectivity, as illustrated by the second example in Scheme 57.233... 

When the alkoxyl radical and the hydrogen to be abstracted are not properly disposed for the Barton reaction, the reactions of the alkoxyl radical, for example -fragmentation, intramolecular addition to the double bond, disproportionation or a-hydrogen fission, and intermolecular hydrogen abstraction, compete with the Barton reaction or result in an exclusive reaction. Among these reactions, /l-frag-... 

The thiocarbonyl group is excellent for radical addition, which takes place on the sulfur atom and leads to a carbon-centred radical stabilised by the a-sulfur atom. The Barton reaction has enjoyed a great many applications. It mainly involves xanthates and provides many useful processes, such as deoxygenation, decarboxylation, addition to multiple bonds, etc. A number of reviews by Crich et al. have appeared [188, 189], and the most recent is due to Zard [190]. 

An interesting process, reminiscent of the Barton reaction, occurs during the radical addition of 7.59A to HFP [205] (Figure 7.59). 

The classical Hunsdiecker conditions using Ag, and modifications using metals such as Hg, Tl, Pb, and Mn(II), are not very synthetically useful because of the use of toxic metals, requirement of high temperature, and poor yields. As a consequence, many variants of greener chemistry have been developed to replace heavy metals. In addition to Barton s radical approaches, Roy et al. developed a metal-free Hunsdiecker reaction where the acid was treated with A-bromosuccinamide (NBS) and a catalytic amount of LiOAc27 or the phase transfer catalyst (PTC) tetrabutylammonium trifluoroacetate (TBATFA).28-30 As shown below, cinnamic acid 26 was converted to (B-bromostyrene 27 in almost quantitative yield.28 The authors also found that a mixture of 93 7 MeCN/H20 was also a good solvent for the metal-free Hunsdiecker reaction.29 In place of TBATFA, another phase transfer catalyst Select flur was found to be an efficient catalyst for the metal-free Hunsdiecker reaction as well (e.g., 29—>30).31... 

Barton and Crich reported the first examples of the uses of 2-substituted allylic sulfur compounds [53]. Their initial experiments with additions of simple alkyl radicals to allyl sulfides, sulfoxides and sulfones were relatively unsuccessful. This failure was largely due to the fact that the nucleophilic alkyl radicals, which were generated by photolysis of the corresponding Barton ester, underwent addition to a second equivalent of Barton ester faster than they added to the allyl transfer agent. Reactions were much more successful with the electron-deficient acrylate reagent 93 (Fig. 4). Crich was later able to show that this same reagent underwent addition reactions with an acyl radical derived from an acyl phenyl telluride [54]. 

C-Glycopyranosides may be obtained from glycopyranosyl halides via intermolecular addition of glycopyranosyl radicals [129]. In a more useful example, the a-aminoacrylate 192 was used as the radical acceptor for preparation of C-glycosyl amino acids 193 and 194 [130] (Scheme 66). In a concise synthesis of showdomycin (197), Barton utilized the trigger reaction of the 7V-hydroxy-2-thiopyridone derivative and the exceptional radicophilicity of tellurides in concocting the conditions for the conversion from the anisyl telluride 195 to the intermediate 196 after oxidative elimination [131] (Scheme 67). In Keck s synthesis of (-t-)-pseudomonic acid C (201), the intermediate 200 was prepared via stereocontrolled intermolecular addition of the radical generated from the iodide 198 to the allylic sulfone 199 [132] (Scheme 68). 

Radical addition-fragmentation processes have been exploited in synthetic organic chemistry since the early 1970 s. Ally transfer reactions with allyl stannancs and the Barton-McCombic deoxygenation process with xanthates arc two examples of reactions known to involve a S[j2 mechanism. However, the first reports of addition-fragmentation transfer agents in polymerization appeared in the... 

Boron trifluoride catalyses the 1,3-phosphotropic rearrangement of the a-phosphorylated imine (65) to give (66).35 This reaction takes place at room temperature, whereas the uncatalysed reaction requires heating to 150-2000C. High yields of the addition products (67) have been obtained from the reaction of carbon-centred radicals with diphenylvinylphosphine oxide.36 Radical addition to the chiral phosphine oxides (68) using Barton s method provides diastereomeric ratios of up to 9 1 in the case of (69). 

Another useful chain reaction involves the PTOC (pyridine-2-thione-N-oxycarbonyl) esters developed by Barton. Reaction of a carboxylic acid chloride (RCOCl) with the sodium salt on N-hydroxypyridine-2-thione produces an ester designated as R-PTOC. Addition of radical Y" (formed by an earUer initiation step) to the R-PTOC leads to the carboxy radical RCOj. The carboxy radical then decarboxylates to produce the radical R, which can continue the chain reaction or can undergo other reactions. 

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