General Applications in Synthesis

The sterically hindered 4-methyl-2,6-di-r-butylpyridine (MDTBP) has been used to elucidate the mechanism of carbocationic polymerization (80MI3), 

There has been a decisive evolution in the treatment of steric effects in heteroaromatic chemistry. The quantitative estimation of the role of steric strain in reactivity was first made mostly with the help of linear free energy relationships. This method remains easy and helpful, but the basic observation is that the description of a substituent by only one parameter, whatever its empirical or geometrical origin, will describe the total bulk of the substituent and not its conformationally dependent shape. A better knowledge of static and dynamic stereochemistry has helped greatly in understanding not only intramolecular but also intermolecular steric effects associated with rates and equilibria. Quantum and molecular mechanics calculations will certainly be used in the future to a greater extent. 

Heteroaromatics have features in common with aromatic hydrocarbons. But the variety of geometrical situations, the number of heteroatoms and their 

We thank the French CNRS and the Swedish NFR for their support of this work. We are grateful to Professors M. Chanon, A. R. Katritzky, J. Metzger, and J. Sandstrom for helpful advice and encouragement. We acknowledge the help of Miss M. A. Lourdes in preparing the manuscript. 

Hammett, Physical Organic Chemistry, McGraw-Hill, New York, 1940. 

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This reaction has general application in synthesis of 1-, 4- and A -substituted 1,2,3,4-tetrahydroisoquinolines and 1 and 4-substituted isoquinolines. In addition, this reaction has been applied to the synthesis of some alkaloids such as salsoline, salsolidine, carnegine, and lophocerine. ... 

Besides the general application in synthesis of cycloheptatrienes, different bicyclic products—for example, 0-tetralones and azulenones—can be prepared via the intramolecular Buchner ring expansion. 

A variation of Hantzsch s synthesis, using thioureas in conjunction with a-diazoketones in place of a-halogenoketones, has proved to be generally applicable. In this manner, King and MUler (310) obtained 2-amino-4-phenylthiazole in 67% yield. A wide range of 4-substituted 2-aIkyl (or aryl) aminothiazoles and 2-arylimino-3,4-diarylthiazolines have been prepared by Hampel and Muller (627, 665, 666). 

This is the basis of a generally applicable multigram synthesis routes to isolable 1-10 nm organosols of the transition metals that are easily redispersible in high concentration in organic phases (Figure 7) [3,183]. 

Triafulvene 69 was synthesized by an interesting route starting with diphenyl cyclopropenium cation and lithio ethyl acetate72. Although widely used in calicene chemistry (see later) this reaction principle — like the Wittig reaction — did not find general application in methylene cyclopropene synthesis. 

More recent developments in this country have included synthesis of relatively stable oils of low volatility, low pour point, and high viscosity index by esterification of octyl alcohols, such as 2-ethylhexanol, with dibasic acids such as adipic acid and sebacic acid (3). Octyl alcohols may be synthesized from petroleum hydrocarbons via the oxo process. Although of relatively high cost, these synthetic oils find general application in making greases for lubrication of antifriction bearings and instruments in aircraft. 

Bromination-desilylbromination of fS-silyl ketones. The preliminary work on protection of oc,/ -enones by this sequence (8, 196-197) has been perfected in several respects1 and shown to be generally applicable to synthesis of oy8-enones.2 Either bromine or phenyltrimethylammonium tribromide (PTAB, 1,855 2,328 4, 386) can be used. In either case, bromine is introduced mainly at the a-position adjacent to the /1-silyl group. Surprisingly, the undesired a -bromo-/(-silyl ketone is converted to the a-bromo-/)-silyl ketone on exposure to hydrogen bromide at 20°. No other acids can clTccl this conversion. Desilylbromination is generally effected with DBU or F". The sequence is applicable to synthesis of a-methylene ketones (equation I) and lactones. 

Discovered over a century ago, electrophilic mercuration is probably the oldest known C-H bond-activation reaction with a metal compound. The earliest examples of aromatic mercuration were reported by Volhard (mercuration of thiophene) [1], Pesci (mercuration of aromatic amines) [2], and Dimroth [3], who was the first to mercurate benzene and toluene, generalize the reaction, and assign the correct structures to the products originally observed by Pesci. Since the work of Dimroth electrophilic aromatic metalation reactions with compounds of other metals, for example Tl(III), Pb(IV), Sn(IV), Pt(IV), Au(III), Rh(III), and Pd(II), have been discovered [4], In this chapter, we will focus on intermolecular SEAr reactions involving main-group metal electrophiles and resulting in the formation of isolable metal aryls which find numerous important applications in synthesis [5], Well-known electrophilic cyclometalation reactions, for example cyclopalla-dation can be found in other chapters of this book and will not be reviewed here. 

Practitioners of organic photochemistry feel that this science has a great potential for synthesis. Indeed, nowadays many reactions are known that lead to useful transformations and have been exploited as key steps in complex synthetic plans. These achievements attract the interest of synthetic chemists. However, photochemical methods are probably less often adopted than they may be, and are still less familiar to the broad chemical community than other methods. In the present handbook it has been attempted to offer an easy approach to the use of photochemical methods in synthesis. Thus, rather than discussing the chemistry of the various chromo-phores, as usual in photochemistry books, reactions have been grouped according to the molecular transformation involved and care has been given that experimental aspects (much less elaborate with many other methods) are clearly presented. We are convinced that a more general application in nonspecialized laboratories will lead to the discovery of new applications and even new reactions. 

In a general sense, [1,2]-Wittig rearrangements have only a limited application in synthesis because yields and selectivities are frequently moderate at best. For example, the valuable stereoselective conversion of 117 to 118 (which also works with higher homologues) proceeds in only 14% yield.85 86... 

This glance index is provided to assist in the choice of a primary synthesis that may provide a required type of pyrazine derivative from another heterocyclic system. Procedures that afford very poor yields or employ substrates that are difficult of access are omitted so too are those methods that appear to lack general applicability in their present state of development. However, such syntheses are often of great interest and may prove invaluable in the right context. 

Oxymercuration-oxidative demercuration (OM-OD) has considerably broadened the utility of organo-mercurial applications in synthesis. Typically, a solution of the mercurial in DMF (room temperature) was added to a DMF solution of NaBH, through which oxygen was rapidly passed. Generally 1.2-1.3 mol of borohydride was required to effect complete demercuration. In addition to the expected alcohols and hydrocarbons, other products presumed to be alkoxyboron compounds were also formed, but these could be hydrolyzed to alcohols. A typical result is shown in equation (17), with yields after the hydrolysis step. 

So far the di-ir-methane photoisomerization has found few applications in synthesis, despite the fact that vinylcyclopropanes are versatile intermediates. Several reviews discuss Aese compounds from a general point of view. For example, vinylcyclopropanes are prone to rearrange to cyclopentenes. Hence, in sequence, these two rearrangements may serve as a way to produce cyclopentenes from 1,4-dienes. ... 

Although N-protected amino acid mixed anhydrides, and particularly mixed carbonic anhydrides, have been by far the most commonly used mixed anhydrides in peptide synthesis, a number of additional mixed anhydrides derived from acids of phosphorus, arsenic, and sulfur have been reported and used in peptide synthesis t l however, these reagents have not found general applicability in routine peptide synthesis. 

Hydrazoic acid and its alkali metal salts are often used in azide synthesis. Pure hydrazoic acid is violently explosive and the reagent is consequently used in dilute solution in which it is quite stable. Solutions of hydrazoic acid in organic solvents may be conveniently prepared and find general application in azide synthesis " . Silver azide, which has occasionally been used for the preparation of organic azides, is impact sensitive and has been superseded by the alkali metal azides which are not considered explosive under most laboratory conditions. 

The reaction of zinc-copper reagents with acid chlorides has a remarkable generality [7,19] and has found many applications in synthesis (Scheme 9-30) [16,59-64]. The treatment of silyl-protected o-aminated benzylic zinc-copper derivatives such as 33 with an acid chloride leads to a 2-substituted indole 34. Aromatic and heterocyclic zinc compounds provide polyfunctional aromatic or heterocyclic ketones like 35 (see Section 9.6.8 Scheme 9-31) [60]. 

Although this chapter is limited to intermolecular all-carbon reactions, the literature connected to this type of Diels-Alder reactions is still immense. The last general reviews about intermolecular Diels-Alder reactions date from nearly ten years ago - v During the past decade, several reviews were published dealing with specialized topics such as mechanistic aspects , specific dienes 2-35 dienophiles , applications in synthesis " ° and introduction of chirality by using chiral auxiliaries qj- chiral Lewis acids . ... 

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