Hydride method

The condensation is usually carried out by adding a solution containing equimolar amounts of the allyl halide and the aldehyde or ketone to a solution of at least two equivalents of chromium-(II) chloride in THF at 0 5°C. Frequently, the less precious component is used in 50-100% excess. Although commercially available anhydrous chromium(II) chloride can be utilized (Method B), its in situ preparation from chromium(III) chloride and lithium aluminum hydride (Method A) is often preferred. The removal of chromium and aluminum hydroxide, which are formed on aqueous workup, can be accomplished by filtration in the presence of a filtration aid. 

The other way of reducing nitriles to aldehydes involves using a metal hydride reducing agent to add 1 mol of hydrogen and hydrolysis, in situ, of the resulting imine (which is undoubtedly coordinated to the metal). This has been carried out with LiAlH4, LiAlH(OEt)3, LiAlH(NR2)3, and DIBAL-H. The metal hydride method is useful for aliphatic and aromatic nitriles. 

Braman et al. [713] suggested the use of sodium borohydride (NaBH4) as a reducing agent to replace the metallic zinc used in the classical Marsh test, which is awkward to handle and often contains large blanks of the elements of interest. Sodium borohydride is now used almost exclusively in the various modifications of the hydride method. 

Curran2 has reviewed recent applications of the tin hydride method for initiation of radical chain reactions in organic synthesis (191 references). The review covers intermolecular additions of radicals to alkenes (Giese reaction) as well as intramolecular radical cyclizations, including use of vinyl radical cyclization. 

Mannich reaction, 1, 10 7, 3 Meerwein arylation reaction, 11, 3 24, 3 Meerwein-Ponndorf-Verley reduction, 2, 5 Mercury hydride method to prepare radicals, 48, 2... 

Thiocarbonates, synthesis of, 17, 3 Thiocyanation of aromatic amines, phenols, and polynuclear hydrocarbons, 3, 6 Thiophenes, synthesis of, 6, 9 Thorpe-Ziegler condensation, 15, 1 31 Tiemann reaction, 3, 9 Tiffeneau-Demjanov reaction, 11, 2 Tin(n) enolates, 46, 1 Tin hydride method to prepare radicals,... 

LiAIH(OEt)3,345 DIBALH,346 and NaAIH4.347 The metal hydride method is useful for aliphatic and aromatic nitriles. Reduction to the aldehyde has also been accomplished by treatment of the nitrile with sodium hypophosphate and Raney nickel in aqueous acetic acid-pyridine or formic acid,348 and with zinc and a Cob(I)alamin catalyst in aqueous acetic... 

For analyses, an 0.5 g sample is weighed into a porcelain boat and inserted into the combustion tube with an oxygen flow of —30 cc/min. With a cold trap in place, the sample is ignited by heating the combustion tube with a meker burner. The coal sample is allowed to burn freely, and then the temperature is raised to the burner maximum for 5 min. The combustion tube is cooled for 5 min and separated from the condenser section. The condenser is removed from the cold trap and allowed to warm to ambient temperature. Add 10 ml of water to the condenser and flush into a 50 ml volumetric flask. Make to volume with water and mix. Take an aliquot of 15 ml or less containing up to 0.3 fxg of selenium and proceed as in the hydride method for arsenic, tin, and bismuth by AAS, as previously described. 

The radical is generated on the sugar template using mostly the tin hydride method and halo derivatives [72,87,89], thionocarbonate [90-91], or selenium derivatives [91,94, 95]. Again, in these reactions, the kinetically controlled 5-exo cyclization is always... 

The tin hydride method is very valuable for forming a C-C bond by addition of a radical to a C-C multiple bond in intermolecular or intramolecular systems [1,10,11]. Since the general principles of the chain reaction are known, this method is easy to apply. Therefore, one can design the reaction conditions carefully, taking into account the rates of the competing reactions and how the reactivity of the radical and the alkene can be influenced by substituents. Actually, formation of C-glycosides is the first example of the tin hydride method [12,13]. 

The wide versatility of the tin hydride method in carbohydrate chemistry exists because anomeric radicals can be generated from many functional groups at the anomeric... 

The tin hydride method suffers from one major disadvantage, namely the efficiency of the reagent as a hydrogen atom donor. For successful synthesis, alkenes have to be reactive enough, otherwise direct reduction of the starting precursor becomes a considerable side reaction. In practice, the yields are increased by slow addition of a solution of tin hydride and a radical initiator into the reaction mixture containing an excess of alkene. However, a delicate balance must be maintained. If a large excess of olefin is used, polymerization can compete. 2,2-Azobisisobutyronitrile is the most commonly employed initiator, with a half-life time for unimolecular scission of 1 h at 80°C. 

Because no tin hydride is present, intermediate radicals are only slowly intercepted by hydrogen atom abstraction. Thus, the fragmentation method is a clever alternative that avoids this course, and low concentrations are not required. As a result of this, even relatively unreactive precursors, such as glycosyl chlorides and phenylsulfides, can be used. Therefore, the method is compatible with the same molecular complexity and an extended spectrum of functionality as found in the tin hydride method. 

Table 1 The Tin Hydride Method for the Addition of Glycosyl Radicals to Alkenes...

Application of this method opens a way to synthesize C-glycosides 48 and 49, similar to those obtained by the tin hydride method. 

There are several examples of the addition reactions of caibonyl-substituted radicals to alkenes by the tin hydride method. The first reaction cited in Scheme 32 is a clear-cut example of reversed electronic requirement an electrophilic radical pairing with a nucleophilic alkene.60 Because enol ethers are not easily hydrostannylated, the use of a chloride precursor (which is activated by the esters) is possible. Indeed, the use of a bromomalonate results in a completely different product (Section 4.1.6.1.4). The second example is more intriguing (especially in light of die recent proposals on the existence of ambiphilic radicals) because it appears to go against conventional wisdom in the pairing of radicals and acceptors.118,119... 

Radical addition reactions conducted by the mercury(II) hydride method were also pioneered by Giese and are very similar in principle to the tin hydride method. The radical is generated from an organomer-curial (rather than a halide) and removed by hydrogen transfer from a mercury(II) hydride (rather than a tin hydride). Mercury(II) hydride reductions have been covered in several recent reviews.3,5,81,82... 

A useful aspect of the mercury(II) hydride method is that it can be directly coupled with the many standard techniques for heteromercuration of alkenes and cyclopropanes. The resulting overall transformation adds a heteroatom and a carbon atom across the carbon-carbon double bond of an alkene or the carbon-carbon single bond of a cyclopropane. This is a difficult transformation to conduct by standard ionic techniques. An alkene thus becomes an equivalent of synthon (12) and a cyclopropane of synthon (13 Scheme 34). Many equivalent transformations (like haloetherification and phenylselenolactoniza-tion) are available to make precursors for tin hydride mediated additions. 

The mechanism of this transformation is outlined in Scheme 38 and each step has important features. In step 1, the tributyltin radical abstracts the radical precursor X. A possible side reaction, the addition of the tributyltin radical to the allylstannane, is much slower than comparable additions to activated alkenes. Even if this addition occurs, the stannyl radical is simply eliminated to regenerate the starting materials. Thus, for symmetric allylstannanes, this reaction is of no consequence. As a result, the range of precursors X that can be used in allylation is more extensive than in the tin hydride method. Even relatively unreactive precursors like chlorides and phenyl sulfides can be used if they are activated by adjacent radical-stabilizing groups. 

Considerations for synthetic planning are remarkably similar to the tin hydride method. The initial radical can either add to the alkene or add to its own precursor (32). To maximize the addition, it is advisable to use a reactive alkene (typically in excess) and to keep a relatively low concentration of the thiohydroxamate (32) hence the slow addition of the acid chloride. At present, rate constants for the addition of a primary and a tertiary alkyl radical to a thiohydroxamate are known (Scheme 46)38-40 and these are useful in selecting alkene acceptors and in planning reaction conditions. 

Like the tin hydride method, this addition succeeds because of differences in reactivity of the starting and the adduct radicals towards the alkene acceptor.154 Unlike the tin hydride method, there is a loss of... 

This means that there is no potential problem equivalent to the hydrostannation in the tin hydride method. 

The tin hydride method is reductive, and the cyclic radical is almost always trapped by a hydrogen atom. In simple cyclizations, both the radical precursor and the alkene are lost during tin hydride reduction, and this sometimes results in underfunctionalized products, necessitating the introduction of extra functional groups for subsequent transformations. However, in the synthesis of simple molecules, this is often an advantage as steps to remove residual alkenes, carbonyl groups and the like, left by ionic methods of C—C bond formation, are not required. Work-up requires separation of the desired products from the tin by-products (see Section 4.1.6.2.1). 

The use of vinyl radicals (pioneered by Stork)90 and aryl radicals (introduced by Beckwith)91 in the tin hydride method is attractive because these radicals are extremely reactive,92 and often provide excellent yields of cyclic products that contain useful functionality for subsequent transformations. 

Conducting radical cyclizations by fragmentation reactions offers a powerful alternative to the tin hydride method. Instead of. obtaining reduced products, one obtains products of substitution an alkene is regenerated in the fragmentation step. 

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