Versatile methods

One of the most versatile methods for the synthesis of derivatives with the acetylene or cumulene system consists In deprotonatlon of the starting acetylene or cumulene and subsequent reaction of the anionic or organometal1ic intermediate with an electrophilic reagent. 

Treatment of geminal dihalocyclopropyl compounds with a strong base such as butyl lithium has been for several years the most versatile method for cumulenes. The dihalo compounds are easily obtained by addition of dihalocarbenes to double--bond systems If the dihalocyclopropanes are reacted at low temperatures with alkyllithium, a cyclopropane carbenoid is formed, which in general decomposes above -40 to -50°C to afford the cumulene. Although at present a number of alternative methods are available , the above-mentioned synthesis is the only suitable one for cyclic cumulenes [e.g. 1,2-cyclononadiene and 1,2,3-cyclodecatriene] and substituted non-cyclic cumulenes [e.g. (CH3)2C=C=C=C(CH3)2]. 

Several groups have developed procedures for Pd-mediated coupling based on this general chemistry. The variety of such procedures and the range of compounds for which they are applicable suggest that Pd-calalysed coupling is currently the most versatile method for introduction of 2-substituents which cannot be prepared directly from organolithium intermediates. 

The following section describes a versatile method for preparing either symmetri cal or unsymmetrical ethers that is based on the principles of bimolecular nucleophilic substitution... 

Because amides are so easy to prepare this is a versatile method for the prepara tion of amines... 

Gas chromatography is probably the most versatile method for analysing nitroparaffins (93—95), eg, in the presence of nitric acid esters (96). 

The most versatile method of preparing ethers is the Williamson ether synthesis, particularly in the preparation of unsymmetrical alkyl ethers (12,13). The reaction of sodium alcoholates with halogen derivatives of hydrocarbons gives the ethers ... 

The above examples illustrate reactions at an electron-deficient carbon atom. Other 1,1-bielectrophiles allow the direct introduction of a heteroatom into the resultant heterocycle. The most widely applicable and versatile methods for the synthesis of 1,2,5-thiadiazoles and 1,2,5-selenadiazole rely on this approach. 

A versatile method for the synthesis of a variety of five-membered heterocycles and their ring-fused analogs involves the reaction of a neutral 47r-electron-3-atom system with a 27T-electron system, the dipolarophile, which is usually electron deficient in nature. Available evidence, e.g. retention of dipolarophile stereochemistry in the product and solvent polarity exerting only a moderate influence on the reaction, indicates that the cycloaddition proceeds via a concerted mechanism 63AG(E)565, 63AG(E)633, 68JOC2291) and may be represented in general terms by the expression in Scheme 8. 

The loss of one or two (or sometimes more) ring members from heterocyclics, concerted with or followed by formation of a new ring, is a highly versatile method for heterocyclic synthesis. Loss of N2, CO, CO2, S, SO, SO2, H2C=CH2, etc. is common. Diradical or dipolar intermediates are often encountered, and valence isomerization before the actual fragmentation is characteristic for some systems. 

Spectrophotometry-Colorimetry One of most useful and versatile methods but can be time consuming 10- to 10- M (10- with pre-concentration)... 

A versatile method for the direct C-21 halogenation of a 20-ketopregnane was discovered by Ringold and Stork it consists of reaction with iodine-calcium oxide in tetrahydrofuran-methanol, and the resulting 21-iodo compound is displaced by acetate in the usual fashion ... 

The Wittig reaction (Sections 17.12-17.13) Reaction of a phosphorus ylide with aldehydes and ketones leads to the formation of an alkene. A versatile method for the regiospecific preparation of alkenes. 

The most versatile method for preparing enamines involves the condensation of aldehydes and ketones with secondary amines [Eq. (1)]. Mannich and Davidsen (/) discovered that the reaction of secondary amines with aldehydes in the presence of potassium carbonate and at temperatures near 0° gave enamines, while calcium oxide and elevated temperatures were required to cause a reaction between ketones and secondary amines, although usually in poor yield. The introduction by Herr and Heyl 2-4) of the removal of the water produced in the condensation by azeotropic distillation with benzene made possible the facile preparation of enamines from ketones and disubstituted aldehydes. 

The Bischler-Napieralski reaction involves the cyclization of phenethyl amides 1 in the presence of dehydrating agents such as P2O5 or POCI3 to afford 3,4-dihydroisoquinoline products 2. This reaction is one of the most commonly employed and versatile methods for the synthesis of the isoquinoline ring system, which is found in a large number of alkaloid natural products. The Bischler-Napieralski reaction is also frequently used for the conversion of N-acyl tryptamine derivatives 3 into p-carbolines 4 (eq 2). 

The addition of the a-carbon of an enolizable aldehyde or ketone 1 to the carbonyl group of a second aldehyde or ketone 2 is called the aldol reaction It is a versatile method for the formation of carbon-carbon bonds, and is frequently used in organic chemistry. The initial reaction product is a /3-hydroxy aldehyde (aldol) or /3-hydroxy ketone (ketol) 3. A subsequent dehydration step can follow, to yield an o ,/3-unsaturated carbonyl compound 4. In that case the entire process is also called aldol condensation. 

The overall process is the addition of a CH-acidic compound to the carbon-carbon double bond of an o ,/3-unsaturated carbonyl compound. The Michael reaction is of particular importance in organic synthesis for the construction of the carbon skeleton. The above CH-acidic compounds usually do not add to ordinary carbon-carbon double bonds. Another and even more versatile method for carbon-carbon bond formation that employs enolates as reactive species is the aldol reaction. 

The Stork enamine reaction is an important and versatile method for the synthesis of a-substituted aldehydes and ketones. Such products should in principle also be... 

Seqnendal Michael addidons are versatile methods for the constnicdon of cyclic compounds. Although a variety of these reacdons have been developed, the use of alcohols as nucleophiles for the Michael addidon to nltroalkenes has been little studied. Recently, Dteda and coworkers have reported an elegant synthesis of octahydtobett2o[li furans via the seqnendal Michael addidon of 1-nltro-cyclohexenev/ith methyl4-hydroxy-2-bittynoatein the presence of r-BnOK followed by radical denitradon fEq. 7.74. ... 

Carbonyl condensation reactions are perhaps the most versatile methods available for synthesizing complex molecules. By putting a few fundamental reactions together in the proper sequence, some remarkably useful transformations can be carried out. One such example is the Robinson annulation reaction for tire synthesis of polycyclic molecules. The word annulation comes from the Latin annulus, meaning "ring," so an annulation reaction builds a new ring onto a molecule. 

Many different nucleophiles—halide, hydride, cyanide, and hydroxide among others—react with arenediazonium salts, yielding many different kinds of substituted benzenes. The overall sequence of (1) nitration, (2) reduction, (3) diazotization, and (4) nucleophilic substitution is perhaps the single most versatile method of aromatic substitution. 

A novel and versatile method for preparing polymer-supported reactive dienes was recently developed by Smith [26]. PS-DES (polystyrene diethyl-silane) resin 28 treated with trifluoromethanesulfonic acid was converted to a polymer-supported silyl triflate 29 and then functionalized with enolizable a,jS-unsaturated aldehydes and ketones to form silyloxydienes 30 and 31 (Scheme 4.4). These reactive dienes were then trapped with dienophiles and the Diels Alder adducts were electrophilically cleaved with a solution of TFA. 

Radiation methods, pulse radiolysis (22, 23), and 7 irradiation techniques (24) prove to be elegant and versatile methods not only for generation of unstable radicals, but also for the study of their physical properties and reactivity. 

The utility of lOOC reactions in the synthesis of fused rings containing a bridgehead N atom such as pyrrolizidines, indolizidines, and quinolizidines which occur widely in a number of alkaloids has been demonstrated [64]. Substrates 242 a-d, that possess properly positioned aldoxime and alkene functions, were prepared from proline or pipecolinic acid 240 (Eq. 27). Esterification of 240 and introduction of unsaturation on N by AT-alkylation produced 241 which was followed by conversion of the carbethoxy function to an aldoxime 242. lOOC reaction of 242 led to stereoselective formation of various tricyclic systems 243. This versatile method thus allows attachment of various unsaturated side chains that can serve for generation of functionalized five- or six-membered (possibly even larger) rings. 

With the ArH ArTlX2 Arl reaction sequence available as a rapid and reliable probe for aromatic thallation, a detailed study was undertaken of the various factors affecting orientation in this electrophilic metallation process (153). The results, which are summarized below, demonstrate that aromatic thallation is subject to an almost unprecedented degree of orientation control coupled with the ease with which thallium can then be displaced by other substitutent groups (this aspect of the synthetic exploitation of aromatic thallation is discussed in detail below), the sequential processes of thallation followed by displacement represent a new and versatile method for aromatic substitution which both rivals and complements the classic Sandmeyer reaction. 

Coordination polymerization is the most versatile method of preparing PCL and its copolymers, affording high molecular weights and conversions, and either block or random copolymers depending on the conditions. As with the preceding classes of initiators, the product... 

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