Classical conditioning

The classical conditions for the Madelung indole synthesis are illustrated by the Organic Syntheses preparation of 2-methylindole which involves heating o-methylacetanilide with sodium amide at 250 C[1]. 

Another variation of the Madelung synthesis involves use of an O-alkyl or O-silyl imidate as the C2 electrophile. The mechanistic advantage of this modification stems from avoiding competing N-deprotonation, which presumably reduces the electrophilicity of the amide group under the classical conditions. Examples of this approach to date appear to have been limited to reactants with a EW substituent at the o-alkyl group[15,16]. 

The Roussel group has described recently a novel method for the synthesis of 2,2-dimethyl-A" -3-keto steroids. Thus addition of potassium t-butoxide to a solution of 19-nortestosterone (25) in tetrahydrofuran containing methyl iodide and hexamethylphosphorous triamide at —70° affords the 2,2-dimethyl compound (26) in good yield.Methylation of A" -3-ketone by the classical conditions, namely addition of methyl iodide to a solution of the steroid and potassium /-butoxide, leads to the 4,4-dimethyl product. 

In conclusion, the Hofmann-Loffler-Freytag reaction tends to give moderate and sometimes poor yields for the preparation pyrrolidines under the classic conditions. Nonetheless, the utility of this reaction to functionalize molecules via the aminyl radical mechanism plays an unique role in the tool box for the organic chemist, enabling transformations not easily achievable using other means. Furthermore, milder conditions and better yields can be achieved by taking advantages of the newer developments such as the Suarez modification. 

The chemical yield of the classical Henry reaction is not always good and depends on steric factors thus, highest yields are obtained when nitromethane is used. Performing the reaction under high pressure (9 kbar, 30 °C) with tetrabutylammonium fluoride catalysis19 enlarges the scope of the reaction dramatically. Thus, addition of nitropropane to 2-methylcyclohexanone, which is not reactive under the classical conditions, was achieved in 40 % yield. Improved yields... 

The one-pot synthesis of thiazolo[3,4-a]benzimidazoles has been reported using a microwave-assisted condensation-cyclization (see Scheme 17) of a substituted 1,2-diamine, substituted benzaldehyde and mercaptoacetic acid [74]. Heating the mixture at reflux for 12 min using a single-mode microwave reactor for the most part gave the fused benzimidazoles in improved yield and dramatically shorter times, when compared to classical conditions of heating at reflux in benzene for 24-48 h (Scheme 29). 

The application of 1,3-dipolar cycloaddition processes to the synthesis of substituted tetrahydrofurans has been investigated, starting from epoxides and alkenes under microwave irradiation. The epoxide 85 was rapidly converted into carbonyl ylide 86 that behaved as a 1,3-dipole toward various alkenes, leading to quantitative yields of tetrahydrofuran derivatives 87 (Scheme 30). The reactions were performed in toluene within 40 min instead of 40 h under classical conditions, without significantly altering the selectivi-ties [64]. 

The Bischler-Napieralski reaction has been described to proceed imder microwave irradiation to give very good yields of dihydroisoquinolines [140] and other polycyclic compounds (see below) in the presence of POCI3 and P2O5 (classical conditions) in toluene (10 cycles of 60 s each using a dedicated microwave reactor). 

Childress AR, McLellan AT, Ehrman R, et al Classically conditioned responses in opioid and cocaine dependence a role in relapse NIDA Res Monogr 84 23 3, 1988... 

One of the most studied applications of Catalytic Membrane Reactors (CMRs) is the dehydrogenation of alkanes. For this reaction, in conventional reactors and under classical conditions, the conversion is controlled by thermodynamics and high temperatures are required leading to a rapid catalyst deactivation and expensive operative costs In a CMR, the selective removal of hydrogen from the reaction zone through a permselective membrane will favour the conversion and then allow higher olefin yields when compared to conventional (nonmembrane) reactors [1-3]... 

The replacement of a halide or sulfonate by cyanide ion, extending the carbon chain by one atom and providing an entry to carboxylic acid derivatives, has been a reaction of synthetic importance since the early days of organic chemistry. The classical conditions for preparing nitriles involve heating a halide with a cyanide salt... 

Aryl Halides from Diazonium Ion Intermediates. Replacement of diazonium groups by halides is a valuable alternative to direct halogenation for the preparation of aryl halides. Aryl bromides and chlorides are usually prepared by a reaction using the appropriate Cu(I) salt, which is known as the Sandmeyer reaction. Under the classic conditions, the diazonium salt is added to a hot acidic solution of the cuprous halide.99 The Sandmeyer reaction occurs by an oxidative addition reaction of the diazonium ion with Cu(I) and halide transfer from a Cu(III) intermediate. 

Some other examples of metal-catalyzed substitutions are given in Scheme 11.10. Entries 1 to 3 are copper-catalyzed reactions. Entry 1 is an example of arylation of imidazole. Both dibenzylideneacetone and 1,10-phenanthroline were included as ligands and Cs2C03 was used as the base. Entry 2 is an example of amination by a primary amine. The ligand used in this case was (V,(V-diethyl sal icyl amide. These conditions proved effective for a variety of primary amines and aryl bromides with both ERG and EWG substituents. Entry 3 is an example of more classical conditions. The target structure is a phosphodiesterase inhibitor of a type used in treatment of asthma. Copper powder was used as the catalyst. 

If we are to harness the placebo effect and make use of it in clinical practice, we first have to understand how it works. A number of factors have been proposed as explanations of the placebo effect. These include the relationship between doctors and patients, the patient s beliefs and expectations, the production of opiates in the brain, and a phenomenon called classical conditioning, in which people come to associate pills and injections with therapeutic effects, just as Pavlov s dogs came to associate the sound of a bell with the presentation of food. In this chapter we look at how all of these processes combine to produce placebo effects, and we consider their implications for the treatment of depression. 

The 1897 study in which Pavlov s student substituted a glass of water for the carbon bisulphide that had been used to stimulate the dogs to salivate shows the relevance of classical conditioning to the placebo effect. The glass of water was a placebo. Although it was inert, it looked exactly like the substance that had led the dogs to salivate. 

Here then is the classical conditioning account of the placebo effect. People experience getting better after having been given active medications. These medications are always administered in some kind of vehicle - in a pill, a capsule or by injection. Eventually the pills, capsules and injections become associated... 

Many of these reports are, however, based on inaccurate or unfounded comparisons with classical conditions which do not enable unequivocal conclusions to be drawn about the effects of microwaves. For this reason, apparent contradictions and controversies have appeared in the literature [5-7]. To try to rationalize all of these results it is necessary to propose a plausible interpretation of effects based on accurate... 

Rapid and easy reactions occur, even with the most hindered mesitoic esters, which are otherwise practically nonsaponifiable under classical conditions [65],... 

Under classical conditions, the reaction between 3 and styrene required 50 h of heating at 110 °C, and gave the dihydropyridazine adduct 10a [24], After SMWI with 30 W incident power for 5 min (Tmax = 154 °C), the adduct 10a was not detected whereas the totally dehydrogenated product, pyridazine 10b, was isolated in almost quantitative yield (Tab. 7.1, entry 8). Ethyl vinyl ether and 3 gave the same product, pyridazine 11, under both classical heating [25] and MW irradiation conditions (Tab. 7.1, entry 9). In this instance the DA adduct lost nitrogen and ethanol. 

Another example of the retention of volatile DA reagents is that of cyclopentadiene in a tandem retro-DA/DA prime reaction [15, 16, 38], This reaction type is the thermal decomposition of a DA adduct (A) and the generation of a diene (generally the initial diene) which is trapped in situ by a dienophile leading to a new adduct (B) [39]. Cyclopentadiene (22) (b.p. 42 °C) is generated by thermolysis of its dimer at approximately 160 °C [40]. An equimolar mixture of commercial crude dicyclopenta-diene (21) and dimethyl maleate was irradiated in accordance with the GS/MW process, in an open reactor, under 60 W incident power, for 4 min (8 x 30 s). The expected adduct 23 was isolated in 40% yield (Scheme 7.1). The isomeric composition of 23 (endo-endoIexo-exo = 65/35) was identical with that obtained under classical conditions from 22 and methyl maleate [41]. The overall yield of this tandem reaction can be increased from pure dimer 21 (61%) and the same tandem reaction has also been reported using ethyl maleate as dienophile [31]. 

Unfortunately, the comparison is not reliable because the temperature was not measured in the domestic oven. Dioxolane formation by acid-catalyzed exchange between 2,2-dimethyl-l,3-dioxolane (DMD) and a ketone in a inert solvent, or simply in excess DMD, requires 4 to 7h under classical conditions [63], This reaction is readily achieved under microwave irradiation in high yields in 4 to 30 min (Scheme 8.43). 

The transesterification of phenyl-/J-D-glucoside catalyzed by Sulfolobus solfataricus [81b] was quantitative within 2 h at 110 °C under the action of irradiation whereas the yield was only 60% after 40 h under classical conditions (Scheme 8.57). 

In an attempt to prepare new diprenorphine analogs, Linders, in one of the first examples of microwave-induced organic reactions, reported the reaction between methyl vinyl ketone and 6-demethoxy-/J-dihydrothebaine (48) [53], The Diels-Alder reaction, when performed under classical conditions, led to extensive polymerization of the dienophile. A dramatic improvement was achieved when the cycloaddition was conducted in a modified microwave oven at the reflux temperature of methyl vinyl ketone. By use of these conditions adducts 49 and 50 were obtained in a 3 2 ratio, according to HPLC (Scheme 9.12). 

The reaction proceeds even with a very poor dienophile such as ethyl phenylpro-piolate (73), which does not react under classical conditions. 

In 1991 Bose described the synthesis of ot-vinyl /1-lactams by reaction of ,/l-unsa-turated acyl chlorides with a Schiff base in chlorobenzene under microwave irradiation (an example of the eco-friendly MORE chemistry, in which only a limited amount of solvent is used) [20b]. Under these conditions, a-vinyl /1-lactam formation can be achieved in 65-70% in approximately 5 min (classical conditions require several hours and lead only to modest yields). 

A rapid approach to ot-amino /1-lactams has been developed by Bose and uses the tetrachlorophthalimido group as a masked amino substituent (Scheme 9.70) [118]. The trans /1-lactam 218a could be obtained almost exclusively in 98% yield after 3-5 min under strong microwave irradiation. Under classical conditions the cis isomer (218a 218b = 10 90) is obtained in 52% yield. 

D. M. P. Mingos, A. G. Whittaker, Microwave Dielectric Heating Effects in Chemical Synthesis in Chemistry under Extreme or non-Classical Conditions,... 

R. van Eldik and C. D. Hubbard (Eds.), Chemistry Under Extreme or Non-Classic Conditions, Spektrum Academischer Verlag, Heidelberg Wiley, New York, in press. 

Taylor, K.S., G.D. Waller, and L.A. Crowder. 1987. Impairment of a classical conditioned response of the honey bee (Apis mellifera L.) by sublethal doses of synthetic pyrethroid insecticides. Apidologie 18 243-252. Theophilidis, G., M. Benaki, and E. Papadopoulu-Mourkidou. 1997. Neurotoxic action of six pyrethroid insecticides on the isolated sciatic nerve of a frog (Rana ridibunda). Comp. Biochem. Physiol. 118C 97-103. Tippe, A. 1987. Evidence for different mechanisms of action of the three pyrethroids, deltamethrin, cypermethrin, and fenvalerate, on the excitation threshold of myelinated nerve. Pestic. Biochem. Physiol. 28 67-74. 

The classical Friedel-Crafts approach toward attaching a phosphorus site directly to an aromatic ring would seem a promising route. Phosphorus-centered acid halides would be anticipated to participate in electrophilic aromatic substitution much in the manner of ordinary acyl halides. Early efforts confirmed this concept.48-52 However, difficulties have been encountered in the use of the classical conditions,53 and modifications to the approach have been necessary. 

We now turn to the quantum version of these results. In this case, the analogous cumulant expansion gives exactly the same equations for the centroids as above, while the equations for the higher cumulants are different. We can again investigate whether a trajectory limit exists. Localization holds in the weakly nonlinear case if the classical condition above is satisfied. In the case of strong nonlinearity, the inequality becomes... 

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