By Direct C-Alkylation

For convenience, this alkylation section is subdivided into two subsections, the first covering various regular C-alkylation processes and the second outlining some typical C-alkylations as used in the Schollkopf synthesis. 

This process has been performed in many way to convert pyrazines or hydropy-razines into their C-alkylated derivatives. One particular form of such alkylation has been used extensively as the first step in making optically active a-amino acids by the SchoHkopf synthesis. This involves, for ex- 

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Allylphenols and derivatives with substituents in the allyl group can, be prepared by direct C-alkylation of the sodium salt of the phenol in benzene solution.16 This method is not as good for the preparation of allylphenols themselves as the one involving preparation of the allyl ether followed by rearrangement, because a mixture of several products is obtained in C-alkylation. Thus the alkylation of p-cresol in benzene with sodium and allyl bromide yields 20% of allyl 4-methylphenyl ether, 8% of allyl 2-allyl-4-methylphenyl ether, 40% of 2-allyl-4-methyl-phenol, and 15% of 2,6-diallyl-4-methylphenol.16 The rearrangement of allyl 4-methylphenyl ether, however, yields 2-allyl-4-methylphenol in practically quantitative yield, and the ether is easily obtained. 

In the corresponding reaction with allylic halides, -alkylated products were formed by direct C-alkylation as well as by N-alkylation followed by N - C [3,3]sigmatropic... 

Cyclopentenone amelation,1 A new method for this reaction involves Pd(0)-directed C-alkylation of 2-mcthyl-1,3-cyclopentanedione or 2-methyl-l,3intramolecular Wittig reaction (equation I). Of special interest, the cyclopentenone 1 can be obtained in optically active form by use of an optically active phosphine. Thus use of (R)-DIOP (4, 273 5, 360- 361 6, 309) leads to 1 as a 70 30 mixture of ( + )- and (-)-enantiomers. Similar results arc obtained with (R)-(-)-methylphenylprop>i-phosphine. 

A new synthesis of ( )-menthofuran (155) has been described which involves a three-step reaction sequence from the cyclohexanone (152) via direct C-alkylation with ethyl 2-iodopropionate to give (153) (Scheme 35). Hydrolysis of the diester (153) with hydrochloric acid afforded 3,6-dimethyl-2,4,5,6,7,7a-hexahydrobenzofuran-2-one (154). The final step in the sequence was the conversion of the a,/3-unsaturated y-lactone ring into the furan ring by reduction with lithium aluminum hydride and 2-propanol to afford (i)-menthofuran (155) in satisfactory yield (80JOC1517). 

Such ketones have been made by direct C-acylation of alkyl-1,5-naphthyridines (see Section 2.2.2). 

Two explanations have been suggested for this anomalous result83,84. Huffman and coworkers84 have proposed that the 2,2-disubstituted cyclohexanone (38) is derived directly from a 2,6-disubstituted enolate intermediate by simultaneous alkylation at C2 and dealkylation at C6. This is in effect a S 2 mechanism for which there is no precedent in enamine chemistry (Scheme 24). The basis for this suggestion is the anomalous solvent-dependent annulation of 2-substituted cyclohexanone enamines with methyl vinyl ketone (MVK) and the assumption that direct C-alkylation of a tetrasubstituted enamine is improbable for it is known that there is considerably less overlap of the unshared electrons on nitrogen with the n system of the double bond in this isomer relative to the more stable trisubstituted isomer, thereby greatly decreasing the rate of alkylation . 

Nevertheless, a number of possible pathways which bear good chemical and/or biological analogies have been proposed. For example, presqualene pyrophosphate (77) could be formed via a protonated cyclopropane intermediate (79) by direct electrophilic alkylation of the C(2,3) double bond (Scheme 3), or via a tertiary cation as suggested by... 

An ingenious extension of the Tsuji-Trost reaction was the cornerstone of Oppolzer s enantioselective synthesis of a heteroyohimbine alkaloid, (-t-j-B-isorauniticine (267) [117]. Substrate 263 was prepared from a commercially available glycinate equivalent by Malkylation, installation of the sultam chiral auxiliary followed by a sultam-directed C-alkylation. As illustrated in Scheme 48, the crucial double cyclization was accomplished by the treatment of 263 with Pd(dba), Bu,P, in the presence of carbon monoxide (1 atm) in acetic acid to give enone 264 and two other stereoisomers in a 67 22 11 ratio. In this case, an allyl carbonate, rather than an allyl acetate, was used as the allyl precursor. Since carbonate is an irreversible leaving group, formation of the n-allylpalladium complex occurs readily. In the presence of Pd(0), the allylic carbonate is converted into a n-allylpalladium complex with concurrent release of CO, and... 

Direct C-alkylation of 2-substituted imidazoles with soft alkylating electrophiles has been discussed earlier (see Section 3.02.5.2.6). Attempts to utihze the ylide mechanism of electrophilic substitution in which the acidic and basic properties of imidazole play equal roles are exemplified by the reactions of 2-quinoxalylacetonitriles with 1-alkyl- and 1-aryl-imidazoles to form condensed products (Scheme 22). Dequaternization only occurs when is alkyl <93CHE194>. 

Palladium Catalysts Yu s group has carried out systematic studies on Pd-catalyzed alkylations of aryl C—H bonds. Stille-type cross-coupling reactions have been developed by directed C—H activation (Equation 11.30) [68]. The reaction rate is enhanced by benzoquinone and microwave irradiation. Significantly, carboxylic acid functionality can be used as an efficient directing group for aryl C— H bond activation (Equation 11.31) [69]. The reaction conditions can be applied to the carboxylation of vinyl C— H bonds. The possible intermediacy of a palladacycle has been confirmed by NMR spectra and X-ray crystallography. 

Cross-Linker. It is well known that polyfunctional benzylic alcohols act as good crosslinkers for poly(4-hydroxystyrene) (11). This acid-catalyzed cross-linking reaction was studied in detail, and the reaction was proposed to proceed via a direct C-alkylation as well as an initial O-alkylation, followed by a subsequent acid-catalyzed rearrangement to the final alkylated product. Furthermore, both a thermal cross-linking and an acid-catalyzed cross-linking process were proposed for this alkylation (72). Thus we decided to use 4,4 -methylenebis[2,6-bis(hydroxymethyl)phenol] (MBHP) and 2,6-bis(hydroxy-methyl)phenol (BHP) in conjunction with 1 and 2, respectively, on the basis of its avail-... 

A re-investigation of the reaction between diketen and amides has shown that N-acetoacetylcarboxamides are formed most efficiently in the presence of trimethylsilyliodide. Olefins react with primary amides in the presence of mercury(ii) nitrate to give iV-substituted amides after NaBH4 reduction. The method provides a convenient procedure for the Markovnikov amidation of double bonds yields vary from 17 to 99% over 11 examples. Direct C-alkylation of secondary thioamides is achieved by the reaction of the dianion (177) with an activated halide to give (178). Esters of malonic, cyanoacetic, and /8-keto acids are readily C-amidoethylated by N-acylaziridines in the presence of triethylamine. ... 

A more straightforward access to glycocitrine-II (25) was described by Grundon and Reisch, through direct C-alkylation of 1,3-dihydroxy-lO-methylacridone (19) with one equivalent of the readily available l-bromo-3-methyl-2-butene (281), in tetrahydrofriran at 20°C, in the presenee of alumina in order to prevent O-alkylation (326). The isomeric l,3-dihydroxy-10-methyl-2-(3-methyl-2-butenyl)-acridone (282) and the dialkylated l,3-dihydroxy-10-methyl-2,4-bis(3-methyl-2-butenyl)-acridone (283) were also formed during the reaction. Excess of alkylating agent resulted in the formation of tetracyclic compounds 284 and 285. 

Acetylsucrose [63648-81-7] has been prepared in 40% yield by direct acetylation of sucrose using acetic anhydride in pyridine at 40° C (36). The 6-ester has subsequently been obtained in greater than 90% yield, by way of 4,6-cycHc orthoacetate. Other selective methods for the 6-acylated derivatives include the use of alkyl tin reagents such as dibutyl tin oxide (37) and of dibutyl stannolane derivatives (38). Selective acetylation of sucrose by an enzymic process has also been described. Treatment of sucrose with isopropenyl acetate in pyridine in the presence of Lipase P Amano gave, after chromatography, 6-0-acetylsucrose (33%) and 4/6-di-O-acetylsucrose (8%). The latter compound has been obtained in 47% yield by the prolonged treatment (39). 

Alkenyl zirconium complexes derived from alkynes form C—C bonds when added to aHyUc palladium complexes. The stereochemistry differs from that found in reactions of corresponding carbanions with aHyl—Pd in a way that suggests the Cp2ZrRCl alkylates first at Pd, rather than by direct attack on the aUyl group (259). 

Selectivity, Steering of reaction directions by the type of catalyst cation, eg, O- vs C-alkylation (7), substitution vs dibalocarbene addition (8), as weU as enantioselective alkylations by optical active catalysts (9) have been achieved in some systems. Extensive development is necessary, however, to generate satisfactorily large effects. 

The alkaloids cotamine (259), hydrastinine (261), and berberinal (260), each possessing a grouping formed by interaction of an aldehyde with a secondary amino group in their molecule, are unusual. The Grignard reaction of free base 166 does not occur as readily as that of the corresponding salt 167. Both reactions lead to the alkylated product 168. For example, only 50% of hydrastinine reacts and 50% is regenerated, whereas hydrastinine hydrochloride reacts almost quantitatively (261). The salt undoubtedly contains a C=N double bond. In the case of the free base, the presence of a C=N double bond was not proven, and the reaction probably occurs by direct cleavage of the C—OH bond. 

Anhydrous HBr is available in cylinders (6.8-kg and 68-kg capacity) under its own vapour pressure (24 atm at 25°C) and in lecture bottles (450-g capacity). Its main industrial use is in the manufacture of inorganic bromides and the synthesis of alkyl bromides either from alcohols or by direct addition to alkenes. HBr also catalyses numerous organic reactions. Aqueous HBr (48% and 62%) is available as a corrosive pale-yellow liquid in drums or in large tank trailers (15 0001 and 38 0001). 

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