Radical substitution reactions stereochemistry

Further evidence for a bromine-bridged radical comes from radical substitution of optically active 2-bromobutane. Most of the 2,3-dibromobutane which is formed is racemic, indicating that the stereogenic center is involved in the reaction. A bridged intermediate that can react at either carbon can explain the racemization. When the 3-deuterated reagent is used, it can be shown that the hydrogen (or deuterium) that is abstracted is replaced by bromine with retention of stereochemistry These results are also consistent with a bridged bromine radical. 

The major focus in this chapter will be on synthesis, with emphasis placed on more recent applications, particularly those where regiochemistry and stereochemistry are precisely controlled. The reader is referred to the earlier reviews for full mechanistic information and details of historic interest. Electrophilic addition of X—Y to an alkene, where X is the electrophile, gives products with functionality Y (3 to the heteroatom X. Further transformations of X and/or Y provide the basis for diverse synthetic applications. These transformations include replacement of Y by hydrogen, elimination to form a ir-bond (either including the carbon bonded to X or (3 to that carbon so that X is now in an allylic position), and nucleophilic or radical substitution. Representative examples of these synthetic methods will be given below. This chapter will include examples of heterocycles formed in one-pot reactions where the the initial alkene-electrophile adduct contains an electrophilic group that can react further. Examples of heterocycles formed in several steps from alkene-electrophile adducts will also be considered. Cases in which activation by an external electrophile directly results in addition of an internal heteroatom nucleophile are treated in Chapter 1.9 of this volume. 

Allylation of organic halides. T wo laboratories2 have reported briefly that in the presence of a radical initiator organic halides undergo allylic substitution reactions with allyltrialkyltin compounds in moderate yield. This reaction was used in a recent Synthesis of the neurotoxin (+ )-perhydrohistrionicotoxin (7) to introduce the n-butyl tide chain.3 AI BN-catalyzed reaction of the bromide 2 with 1 proceeds in unexpectedly igh yield and with complete stereocontrol to give a single product 3. It is the tndesired isomer, but the desired stereochemistry is obtained by epimerization of the Intermediate ketone 5. The hydroxy lactam (6) had previously been used for the Synthesis of 7. 

In germanium chemistry the importance of free radical pathways in substitution reactions of secondary bromides with R3GeLi (R = CH3, CgHs) reagents is strongly indicated by product stereochemistry in cyclohexyl systems and by cyclization of the cA-heptene-2-yl moiety to yield [(2-methylcyclopentenyl)methyl]germanes, with the appropriate cis/trans ratio, as shown in equation 180, Table 9 and equations 181 and 182189. 

There are a number of synthetically important applications, involving these heterocycles, as unstable intermediates, which are reviewed here. These applications feature the ability of selenium to be readily extruded from seleniranes and selenirenes, neighboring group participation by / -Se to control the stereochemistry of nucleophilic substitution reactions, and facile, chemoselective replacement of Se by H in radical-induced reactions. 

Radical Cyclization Reactions. The capable radical chain carrying character of tosyl bromide has been applied to the cyclization of several 1,6-dienes. In many examples, the products result from addition of the tosyl radical to the terminus of the less-substituted olefin, followed by S-eAU-tn gcyclization with the second olefin to deliver a five-membered ring product. In all cases, cis-stereochemistry predominates. In some cases, however, the 1,2-addition of tosyl bromide to one olefin is the observed product. The generic reaction sequence is pictured below (eq 2). 

THE STEREOCHEMISTRY OF RADICAL SUBSTITUTION AND RADICAL ADDITION REACTIONS... 

Figure 5. Stereochemical effects of M4 isomerizations on stereochemistries of free radical oxidation Arbuzov, and substitution reactions...

The first three chapters discuss fundamental bonding theory, stereochemistry, and conformation, respectively. Chapter 4 discusses the means of study and description of reaction mechanisms. Chapter 9 focuses on aromaticity and aromatic stabilization and can be used at an earlier stage of a course if an instructor desires to do so. The other chapters discuss specific mechanistic types, including nucleophilic substitution, polar additions and eliminations, carbon acids and enolates, carbonyl chemistry, aromatic substitution, concerted reactions, free-radical reactions, and photochemistry. 

The course of each of the free radical reactions shown in equations 19-21, where fluorine substitution alters the normal trans stereochemistry of addition, is ascnbed to endo fluonne stenc effects... 

From the point of view of both synthetic and mechanistic interest, much attention has been focused on the addition reaction between carbenes and alkenes to give cyclopropanes. Characterization of the reactivity of substituted carbenes in addition reactions has emphasized stereochemistry and selectivity. The reactivities of singlet and triplet states are expected to be different. The triplet state is a diradical, and would be expected to exhibit a selectivity similar to free radicals and other species with unpaired electrons. The singlet state, with its unfilled p orbital, should be electrophilic and exhibit reactivity patterns similar to other electrophiles. Moreover, a triplet addition... 

Entry 5 is an example of the use of fra-(trimethylsilyl)silane as the chain carrier. Entries 6 to 11 show additions of radicals from organomercury reagents to substituted alkenes. In general, the stereochemistry of these reactions is determined by reactant conformation and steric approach control. In Entry 9, for example, addition is from the exo face of the norbornyl ring. Entry 12 is an example of addition of an acyl radical from a selenide. These reactions are subject to competition from decarbonylation, but the relatively slow decarbonylation of aroyl radicals (see Part A, Table 11.3) favors addition in this case. 

The absolute stereochemistry for 150 (entries 2 and 3) was determined by hydrolysis and conversion to known compounds. Assuming a tetrahedral or cis octahedral geometry for the magnesium [110], the product stereochemistry is consistent with si face radical addition to an s-cis conformer of the substrate. This is the same sense of selectivity as that obtained with oxazo-lidinone crotonates or cinnamates suggesting that the rotamer geometry of the differentially substituted enoates is the same. The need for stoichiometric amount of the chiral Lewis acid to obtain high selectivity with 148 in contrast to successful catalytic reactions with crotonates is most likely a reflection of the additional donor atom present in the substrate. 

Photoinduced electron transfer promoted cyclization reactions of a-silyl-methyl amines have been described by two groups. The group of Pandey cyclized amines of type 135 obtaining pyrrolidines and piperidines 139 in high yields [148]. The cyclization of the a-silylated amine 140 leads to a 1 1 mixture of the isomers 141 and 142 [149]. The absence of diastereoselectivity in comparison to analogous 3-substituted-5-hexenyl radical carbocyclization stereochemistry [9] supports the notion that a reaction pathway via a free radical is unlikely in this photocyclization. The proposed mechanism involves delocalized a-silylmethyl amine radical cations as reactive intermediates. For stereochemical purposes, Pandey has investigated the cyclization reaction of 143, yielding... 

Substituted cyclopropane systems also undergo nucleophilic addition of suitable solvents (MeOH). For example, the photoinduced ET reaction of 1,2-dimethyl-3-phenylcyclopropane (112, R = Me) with p-dicyanobenzene formed a ring-opened ether by anti-Markovnikov addition. The reaction occurs with essentially complete inversion of configuration at carbon, suggesting a nucleophilic cleavage of a one-electron cyclopropane bond, generating 113. The retention of chirality confirms that the stereochemistry of the parent molecule is unperturbed in the radical cation 112 " ". 

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