Succesive reactions

For A-(trimethylsilylmethyl)-5-methylisothioureas 262, cycloaddition with carbonyl compounds results in 2-aminooxazolines 263. ° Aliphatic and aromatic aldehydes and ketones can be employed successfully. However, reaction with ketones appears to be poor. Ylide generation with CsF is the method of choice although TBAF and KF have also been used but with lower yields. A polar solvent such as MeCN, DMF, or hexamethylphosphoric triamide (HMPA) is required for a succesful reaction (Scheme 8.73). 

In the flask were succesively placed 0.10 mol of the sulfinate (note 2), 25 ml of dry, pure HMPT (note 3), 4 g of powdered sodium iodide, 40 g of zinc dust and some boiling stones. After swirling for a few seconds the flask was connected with the other parts of the distillation apparatus, the system was evacuated immediately by means of the water pump (note 4) and the flask was then heated cautiously (free flame). A vigorous reaction started suddenly and the cumulene and part of the HMPT passed over. When the distillation had stopped completely... 

Hetero-Diels-Alder reactions have been succesfully employed for the synthesis of arenoquinolizine systems. For example, as shown in Equation 10, treatment of tetrahydroquinoline 319 with Danishefsky s diene 320 in the presence of a Lewis acid gave the benzo[c]quinolizidine derivative 321 <2000JME3718>. 

Reaction rates are macroscopic averages of the number of microscopical molecules that pass from the reactant to the product valley in the potential hypersurface. An estimation of this rate can be obtained from the energy of the highest point in the reaction path, the transition state. This approach will however fail when the reaction proceeds without an enthalpic barrier or when there are many low frequency modes. The study of these cases will require the analysis of the trajectory of the molecule on the potential hypersurface. This idea constitutes the basis of molecular dynamics (MD) [96]. Molecular dynamics were traditionally too computationally demanding for transition metal complexes, but things seem now to be changing with the use of the Car-Parrinello (CP) method [97]. This approach has in fact been already succesfully applied to the study of the catalyzed polymerization of olefins [98]. 

Although in the recent years the stereochemical control of aldol condensations has reached a level of efficiency which allows enantioselective syntheses of very complex compounds containing many asymmetric centres, the situation is still far from what one would consider "ideal". In the first place, the requirement of a substituent at the a-position of the enolate in order to achieve good stereoselection is a limitation which, however, can be overcome by using temporary bulky groups (such as alkylthio ethers, for instance). On the other hand, the ( )-enolates, which are necessary for the preparation of 2,3-anti aldols, are not so easily prepared as the (Z)-enolates and furthermore, they do not show selectivities as good as in the case of the (Z)-enolates. Finally, although elements other than boron -such as zirconium [30] and titanium [31]- have been also used succesfully much work remains to be done in the area of catalysis. In this context, the work of Mukaiyama and Kobayashi [32a,b,c] on asymmetric aldol reactions of silyl enol ethers with aldehydes promoted by tributyltin fluoride and a chiral diamine coordinated to tin(II) triflate... 

On the other hand, the method of Mukaiyama can be succesfully applied to silyl enol ethers of acetic and propionic acid derivatives. For example, perfect stereochemical control is attained in the reaction of silyl enol ether of 5-ethyl propanethioate with several aldehydes including aromatic, aliphatic and a,j5-unsaturated aldehydes, with syir.anti ratios of 100 0 and an ee >98%, provided that a polar solvent, such as propionitrile, and the "slow addition procedure " are used. Thus, a typical experimental procedure is as follows [32e] to a solution of tin(II) triflate (0.08 mmol, 20 mol%) in propionitrile (1 ml) was added (5)-l-methyl-2-[(iV-l-naphthylamino)methyl]pyrrolidine (97b. 0.088 mmol) in propionitrile (1 ml). The mixture was cooled at -78 °C, then a mixture of silyl enol ether of 5-ethyl propanethioate (99, 0.44 mmol) and an aldehyde (0.4 mmol) was slowly added to this solution over a period of 3 h, and the mixture stirred for a further 2 h. After work-up the aldol adduct was isolated as the corresponding trimethylsilyl ether. Most probably the catalytic cycle is that shown in Scheme 9.30. 

The synthetic sequence, which shows only the succesful solutions adopted in every step, is outlined in Scheme 13.1.11. Reaction of l Chloroadamantan-4-one (39) [15] with sodium-potassium alloy in ether gave a mixture of ketonic and hydroxylated material which upon oxidation with Jones reagent gave 7-methylenebicyclo[3.3.1]nonan-2-one (40) in 75% yield. Reduction of 40 with sodium borohydride gave the alcohol 41 which could be also obtained in better yields from l-chloroadamantan-4-one with a large excess of sodium-potassium... 

While a hydroxymethyl group has been succesfully used to temporarily block the lactam nitrogen of halopyridazin-3(2//)-ones such as 191 for Suzuki reactions <2003TL4459>, and the resulting aryl-2-hydroxymethylpyridazin-3(2//)-ones have been immediately deprotected in situ via a base-induced or thermal retro-ene reaction (Equation 39), two recent reports show that Suzuki reaction on unprotected substrates like 5-chloropyridazin-3(2//)-one 192 is feasible (Scheme 47) <2005JME6004, 2006JME2600>. 

The reaction with cyanogen bromide presumably can also be carried out succesfully with ROCLi in Et20-hexane mixtures or with acetylenic Crignard derivatives (at higher temperatures) in Et20 or THF. 

Many classes of perfluoroethers such as acyclic [63], cyclic [64, 65], glymes [66,67], highly branched [63],macrocyclic [68-73], orthoformates [74-76] and poly-ethers [15, 77], have been succesfully prepared in high yield by direct fluorination techniques (Figs. 19 and 20). Carbon-oxygen bond cleavage is minimised in these processes by the addition of an HF scavenger, such as sodium fluoride, to the reaction mixture [14,45,46]. 

Consider the reaction described by eqn. (2) with n = 2 occurring either by two succesive one-electron steps (two possible transition states)... 

Although succesful, this reaction does not lead to polymers of sufficiently high molecular weight to be useful commercially. 

There have been many succesful syntheses of tricyclic structures by Diels-Alder reactions of the o-xylylenols formed from o-alkylphenyl ketones. Below is an intramolecular example aimed at the synthesis of podophyllotoxin [75]. 

Dehydration of 124 to the expected 1-seleno-l-vinylcyclopropanes was succesful only with tertiary alcohols of this type it required the use of thionyl chloride in the presence of triethylamine, pyridine or hexamethylphosphorus triamide followed by reaction with potassium t-butoxide in DMSO, or the use of the Burgess reagent... 

A substantial improvement in the synthesis of steroid /3-D-glucosid-uronic acid derivatives was achieved by Conrow and Bernstein,125 who introduced cadmium carbonate as a new and effective catalyst in the Koenigs-Knorr reaction procedure its use proved to be particularly convenient in the synthesis of such derivatives of phenolic steroids, where the yields obtained by using silver carbonate had not usually exceeded 10%. Thus, by employing cadmium carbonate, several succesful syntheses in the series of phenolic steroids have been claimed (see, for example, Ref. 126). 

In spite of the elegant solution to the problem as represented in the structure of 206, it is rather far from being optimal. In fact, the presence of the naphthalene system in this base made the latter rather vulnerable to electrophilic attack directed at aromatic rings. Owing to this complication, 206 is used in syntheses less often than other sterically hindered bases like 4-methyl-2,6-di-tcrt-butylpyridine 207, ethyldiisopropylamine, 208 (Hunig s base) or ethyldi-cyclohexylamine 209. All of these reagents are now manufactured commercially and widely used in cases where it is essential to carry out a reaction with strong electrophiles under strictly non-acidic conditions with the removal of proton acids as they are formed. In fact, the preparation of 205 was succesfully carried out in the presence of 208. °... 

To calculate the burnout time of char particles, a reaction model is required. With the assumptions that the reaction is mass transfer limited and that it occurs in two succesive steps with CO as intennediate, the burnout time t of a particle can be theoretically derived as (Smolda-s [9], Baeyens et al. [10]) ... 

PTGL-technology can only be succesful if practical solutions are found for problems such as refuse handling and feeding, maintenance of stable operating conditions with a constantly variable feedstock, smooth elimination of residue and proper treatment of reaction products. Quite normally process developers center all their energy on the design,construction and demonstration of their plant and equipment. 

Reactions with nucleotides have also been carried out in ionic liquids. In this context, the transesterification of iV-acetyl-L-phenylalanine ethyl ester with n-propanol catalysed by subtilisin (previously precipitated and rinsed with n-propanol) was succesfully carried out in [bmim+][PFg ] and [bmim+][BF ] (Fig. 7.4) [23]. 

Reduction of A7-nitropyrazole into A -aminopyrazole has been succesfully achieved by lithium aluminum hydride <92AQ724>. Reactions of l-nitro-3,5-dimethyl-4-halopyrazoles (195) with dbu and dbn affords derivatives (196) <94X865>. Reaction of 5-chloro-2-nitroindazole with amines affords 3-amino-5-chloroindazoles <85Phaio5>, while 2,5-dinitroindazole on treatment with A -methylpiperazine affords 3,5-dinitroindazole and 3-(7V-methylpiperazino)-5-nitroindazole <94PHA319>. 

This conclusion holds especially for the examples of relative complex cure processes shown above. Less complex reactions with pure, low molecular weight components can often succesfully be studied using the exothermic reaction effect. 

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