General Synthesis Methods

Ichikawa J (2000) gem-difluoroolefin synthesis general methods via thermostable difluoro-vinylmetals starting from 2,2,2-trifluoroethanol derivatives. J Fluorine Chem 105 257-263... 

A general method for the synthesis of l -alkenes is provided by the action of a Grignard reagent upon allyl bromide, for example ... 

An important general method of preparing indoles, known as the Fischer Indole synthesis, consists in heating the phenylhydrazone of an aldehyde, ketone or keto-acld in the presence of a catalyst such as zinc chloride, hydrochloric acid or glacial acetic acid. Thus acrtophenone phenylhydrazone (I) gives 2-phenyllndole (I V). The synthesis involves an intramolecular condensation with the elimination of ammonia. The following is a plausible mechanism of the reaction ... 

The most general methods for the syntheses of 1,2-difunctional molecules are based on the oxidation of carbon-carbon multiple bonds (p. 117) and the opening of oxiranes by hetero atoms (p. 123fl.). There exist, however, also a few useful reactions in which an a - and a d -synthon or two r -synthons are combined. The classical polar reaction is the addition of cyanide anion to carbonyl groups, which leads to a-hydroxynitriles (cyanohydrins). It is used, for example, in Strecker s synthesis of amino acids and in the homologization of monosaccharides. The ff-hydroxy group of a nitrile can be easily substituted by various nucleophiles, the nitrile can be solvolyzed or reduced. Therefore a large variety of terminal difunctional molecules with one additional carbon atom can be made. Equally versatile are a-methylsulfinyl ketones (H.G. Hauthal, 1971 T. Durst, 1979 O. DeLucchi, 1991), which are available from acid chlorides or esters and the dimsyl anion. Carbanions of these compounds can also be used for the synthesis of 1,4-dicarbonyl compounds (p. 65f.). 

Primary and secondary amines are susceptible to oxidation and replacement reactions involving the N—H bonds. Within the development of peptide synthesis numerous protective groups for N—H bonds have been found (M, Bodanszky, 1976 L.A. Carpino, 1973), and we shall discuss five of the more general methods used involving the reversible formation of... 

In the diester method a deoxynucleoside-5 -monophosphate is condensed with the 3 -OH group of a deoxynucleotide to produce a 3, 5 -phosphodiester. This is illustrated by a general method for dinucleotide synthesis developed by H.G. Khorana (K.L. Agarwal, 1976). One N-... 

In 1888, Hantzsch and Traumann (102) described a general method of synthesis for 2-aminothiazoles (67) by condensation of thiourea with... 

Although this reaction is useful for preparing a ammo acids (Table 22 3 fifth entry) it IS not a general method for the synthesis of amines Its major limitation is that the expected primary amine product is itself a nucleophile and competes with ammonia for the alkyl halide... 

Preparation of phenols Heating its aqueous acidic solution converts a diazonium salt to a phenol This IS the most general method for the synthesis of phenols... 

Preparation of aryl iodides Aryl diazonium salts react with sodium or potassium iodide to form aryl iodides This is the most general method for the synthesis of aryl iodides... 

Miscellaneous Reactions. Sodium bisulfite adds to acetaldehyde to form a white crystalline addition compound, insoluble in ethyl alcohol and ether. This bisulfite addition compound is frequendy used to isolate and purify acetaldehyde, which may be regenerated with dilute acid. Hydrocyanic acid adds to acetaldehyde in the presence of an alkaU catalyst to form cyanohydrin the cyanohydrin may also be prepared from sodium cyanide and the bisulfite addition compound. Acrylonittile [107-13-1] (qv) can be made from acetaldehyde and hydrocyanic acid by heating the cyanohydrin that is formed to 600—700°C (77). Alanine [302-72-7] can be prepared by the reaction of an ammonium salt and an alkaU metal cyanide with acetaldehyde this is a general method for the preparation of a-amino acids called the Strecker amino acids synthesis. Grignard reagents add readily to acetaldehyde, the final product being a secondary alcohol. Thioacetaldehyde [2765-04-0] is formed by reaction of acetaldehyde with hydrogen sulfide thioacetaldehyde polymerizes readily to the trimer. 

A potentially general method of identifying a probe is, first, to purify a protein of interest by chromatography (qv) or electrophoresis. Then a partial amino acid sequence of the protein is deterrnined chemically (see Amino acids). The amino acid sequence is used to predict likely short DNA sequences which direct the synthesis of the protein sequence. Because the genetic code uses redundant codons to direct the synthesis of some amino acids, the predicted probe is unlikely to be unique. The least redundant sequence of 25—30 nucleotides is synthesized chemically as a mixture. The mixed probe is used to screen the Hbrary and the identified clones further screened, either with another probe reverse-translated from the known amino acid sequence or by directly sequencing the clones. Whereas not all recombinant clones encode the protein of interest, reiterative screening allows identification of the correct DNA recombinant. 

From the foregoing discussion it is evident that the most general methods for the synthesis of pyrazines, quinoxalines and phenazines fall into type A and type B categories, but other methods do exist. Although most of these are not of such general applicability, they are worthy of comment. 

The concept of a 1,5-dipolar cyclization gives rise to a general method for the synthesis of an appreciable number of heterocyclic systems. 1,5-Dipoles are derived from 1,3-dipoles by conjugation with different double bond systems, and it is possible to derive 98 theoretically possible 1,5-dipolar systems. The general expression for a 1,5-dipole and some possible combinations of double bond systems are shown in Scheme 14. 

Schemes 110-113 outline the most common general methods for accomplishing the synthesis of thiiranes by formation of a C—S bond (75RCR138,66CRV297, 64HC(19-1)576). The methods in Schemes 111-113 are variations of Scheme 110 they differ in the details of the generation of the thiolate anion which effects the ring closure by a displacement reaction. The methods of converting oxiranes to thiiranes, to be discussed separately (Section 5.06.4.3), involve a displacement like thafof Scheme 110 as the final step.

The procedure described here serves to illustrate a new, general method for effecting the < -arylation of g-dicarbonyl compounds by means of an aryllead triacetate under very mild conditions. Although the first synthesis of an aryllead triacetate was reported relatively recently, a wide range of these compounds can now be readily prepared. The most direct route to these compounds is plumbation of an aromatic compound with lead tetraacetate, and in the procedure reported here p-methoxyphenyllead triacetate has been prepared in this way. It may also be obtained by reaction of the diarylmercury with lead tetraacetate, a longer, but more general method of synthesis of aryllead triacetates. 

In recent years the application of photocycloaddition reactions to organic synthesis has been growing in importance. - The procedure described is illustrative of a general method based on a photocycloaddition reaction for the introduction of an activated alkyl group specifically to the a-carhon atom of an a,/3-unsaturated cyclohexenone. Especially significant is the fact that the method is also applicable to... 

There are three general methods of interest for the preparation of vinyl chloride, one for laboratory synthesis and the other two for commercial production. Vinyl chloride (a gas boiling at -14°C) is most conveniently prepared in the laboratory by the addition of ethylene dichloride (1,2-dichloroethane) in drops on to a warm 10% solution of sodium hydroxide or potassium hydroxide in a 1 1 ethyl alcohol-water mixture Figure 12.1). At one time this method was of commercial interest. It does, however, suffer from the disadvantage that half the chlorine of the ethylene dichloride is consumed in the manufacture of common salt. 

The fourth of Pedersen s general methods is expressed as method Y. In this approach, a single unit may be both nucleophile and electrophile and react with the corresponding portions of its counterpart to yield a macrocycle. This is illustrated in Eq. (3.6). Note that there are really two possibilities here. The first of these is that two units will react as illustrated, but the other possibility is that the single unit will cyelize to afford a crown of half the size. It is precisely this approach which Pedersen used in the first synthesis of 18-crown-6 (see Sect. 3.2). 

Synthesis of bicuculline and nitroadlumine. Groenewoud and Robinson synthesised bicuculline by the general method devised by Hope and Robinson, the initial products in this case being 6-nitro-3 4-methylene-dioxyphthalide (IV) prepared by a new method from normeconin, and hydrastinine (V). The condensation produet, called nitro-a -bicuculline (the X indicating that the dZ-product eannot yet be allocated to the a- or )3-stereoisomeric series cf. synthesis of hydrastine, p. 167), forms minute yellow needles, sinters at 176° and decomposes at 179°. It was reduced to amino-a -bicuculline (I R = NHj), yellow prisms, m.p. 208—4°, the latter... 

A complete synthesis of di-heliotridane has been effected by Prelog and Zalan, 2 using Prelog s general method for the synthesis of dicyclic amines, the proximate, primary material in this case being 1 7-dibromo-4-amino-3-methylheptane hydrobromide,... 

Formation of oxiranes on the sterically more hindered side of the steroid ring system is usually carried out via /raw -halohydrins which afford oxiranes on treatment with base (c -Halohydrins yield ketones on exposure to base). Two general methods are available for the synthesis of tm s-halohydrins (1) the reduction of a-halo ketones and (2) the addition of a hypohalous acid to unsaturated steroids. 

Few procedures are available for the synthesis of steroid thiiranes because the rigidity of the steroid nucleus prohibits the application of many methods of thiirane synthesis. The only general methods involve the con-... 

Several routes to 2,3-diketones have been reported. The most practical and general method is that of Ruzicka, Plattner and Furrer as adapted by Nace and Nelander for synthesis of the diosphenol corresponding to 5a-pregnane-2,3,20-trione (44) starting from 5a-pregnane-3,20-dione (40). The overall yield of diosphenol (44) by this route is 62% based on... 

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