Alkylation Methods

All attempts to prepare selenazole derivatives by the Gatterman (for-mylation) or Friedel-Crafts (alkylation) methods failed (19, 26). indicating that the electrophilic reactivity of the 5-position is less than that of benzene or toluene. 

The activation of CDI by TV-alkylation (method B) has been used for the reaction between carboxylic acids or TV-protected amino acids and alcohols to give the esters in excellent yields.[143] Under the following conditions, which are free of any acids and stronger bases no racemization was observed. 

HZ Sommer, HI Lipp, LL Jackson. Alkylation of amines. A general exhaustive alkylation method for the synthesis of quaternary ammonium compounds, (effects of hindrance) J Org Chem 36, 824, 1971. 

Methylenesulphones are more acidic than the simple esters, ketones and cyano compounds and are more reactive with haloalkanes [e.g. 48-57] to yield precursors for the synthesis of aldehydes [53], ketones [53], esters [54] and 1,4-diketones [55] (Scheme 6.4). The early extractive alkylation methods have been superseded by solidtliquid phase-transfer catalytic methods [e.g. 58] and, combined with microwave irradiation, the reaction times are reduced dramatically [59]. The reactions appear to be somewhat sensitive to steric hindrance, as the methylenesulphones tend to be unreactive towards secondary haloalkanes and it has been reported that iodomethylsulphones cannot be dialkylated [49], although mono- and di-chloromethylsulphones are alkylated with no difficulty [48, 60] and methylenesulphones react with dihaloalkanes to yield cycloalkyl sulphones (Table 6.5 and 6.6). When the ratio of dihaloalkane to methylene sulphone is greater than 0.5 1, open chain systems are produced [48, 49]. Vinyl sulphones are obtained from the base-catalysed elimination of the halogen acid from the products of the alkylation of halomethylenesulphones [48]. 

Moreover, from the environmental standpoint, advantages must be seen on the global balance the DMC-mediated alkylation reactions are much safer than any other alkylation method known that uses conventional reagents. Not only the features of the reaction itself, but the peculiarity of the reagent(s), the base (truly catalytic), and the absence of wastes are also key aspects. 

Compound 10 was converted into allyl glycoside 11 in 73 yield in two steps, (a) Bu2Sn0CH2CH=CH2—SnCl,(4), and (b) MeONa—MeOH. Treatment of 11 with dimethoxypropane and TsOH, and then with benzyl bromide— NaH—DMF afforded compound 12 in 51% yield. Solvolysis of compound 12 in MeOH—AcOH, and then monobenzylation by the stannylation— alkylation method(5) gave the desired glycosyl acceptor 8 in 67% yield. Acetylation of compound 8 and then deallylation with PdCl2— AcONa in aq.AcOH(6) afforded a 93% yield of hemiacetal 13, which was treated with (a) SOCI2—DMF in dichloroethane(7) and (b) AgF— CH CN(8) to give the desired fluoride 9 in 73% overall yield. 

Skiles and Cava have investigated the alkylation method of isoquinoline Reissert compounds (76), performing a comparative study on the alkylation of... 

The Reissert alkylation method was also utilized for synthesizing the basic skeleton of protoberberine alkaloids (Scheme 21). Reaction of 3,4-dihydroiso-quinoline derivatives 149, 150, and 151 with 2-chloromethylbenzoyl chloride and trimethylsilyl cyanide in methylene chloride gave the corresponding 2-chloromethylbenzoyl-l,2,3,4-tetrahydroisoquinaldonitriles (152, 153, and 154,... 

An alternative and possibly more simple approach to S-prenylation is based on S-alkylation of suitably protected or unprotected peptides. This method is widely applied particularly when small amounts of S-prenylated peptides are required, whereby preparative RP-HPLC is generally applied for the isolation of the lipopeptides. The S-alkylation methods used are generally those described above. Whilst with suitably protected peptides solubility represents a major problem, which can be bypassed by S-alkylation of the peptide on resin, 61 with unprotected peptides a very efficient tuning of the reaction conditions is required... 

Recently, both enantiomeric forms of callosobruchusic acid (170), a pheromone of the azuki bean weevil, Callosobruchus chinensis L., which induces the male to extrude his genital organ and to attempt copulation, were synthesized by Mori et al.178), applying Evan s alkylation method in natural product synthesis as the key step. Thus, (S)-prolinol propionamide was converted to its enolate (164) by treatment with LDA. 

In a useful extension of the direct alkylation method, ellipsoidal cryptands have been prepared from dimethylated cyclic diamines by the stepwise quaternization-demethylation sequence shown in Scheme 4 <81 H.3039). 

The alkylation method developed by Fukuzawa et al.245 (see Section 5.2.4) has been used in cyclialkylation to synthesize polycyclic aromatic hydrocarbons such as benzopentaphene 107 [Eq. (5.134)].341... 

Ab initio methods also appear to be useful for predicting the M- to P-conformational transition barrier for reactive species, such as enolate 8. It is known that the presence of an (iS7-C3-substituent will favor the /17-con former in which the C-3 substituent adopts a pseudoequatorial arrangement. Consequently, deprotonation of C-3 at low temperature of certain benzodiazepines can result in single, conformationally chiral, nonracemic enolates locked in the /(/-configuration. The inversion barrier for enolate 8 at 195 K is calculated by DFT methods to be 17.5 kcal mol-1, which compares with 12.4 kcal mol-1 for the derivative where the N-l group is methyl instead of isopropyl <2003JA11482>. These results were used to explain the enantioselective C-3-alkylation method discussed in... 

Methylation of alkaloids containing either phenolic hydroxy groups or secondary amine functions is the most common procedure for converting such alkaloids to known derivatives many examples are given in Section II,C. Diazomethane is the reagent of choice for O-methylation, and diazoethane for O-ethylation. It is possible to effect O-alkylation in the presence of secondary amine functions, as in the conversion of peinamine to its trideuteriomethyl ether (Section II,C,92) and of A-desmethylthalrugosidine to the O-ethyl ether (Section II,C,29). Another O-alkylation method, exemplified by the preparation of O-methyl, O-ethyl, and O-isopropyl ethers of berbamine (364), consisted of heating the alkaloid in... 

N-propinylazoles of the BAY d 9603 type have a close structural relationship to the tritylazoles. They have a wide range of activity, particularly effective against mould fungi. Starting material here is the readily available diphenyl-propinol obtained by ethinyla-tion of benzophenone. The method for the conversion of this carbinol into the corresponding N-substituted imidazole is the reaction with carbonyl or thionyl-bis-imidazole, or preferably with the tris-imidazolide of phosphoric acid in a polar solvent. All other alkylation methods in which carbocations occur as intermediates completely fail. 

This compound ((3R,3 i )-(P,P)-trans-1,1, 2,2, 3,3, 4,4 -octahydro-3,3 -dimcthyl-4,4 -biphenanthrylidene, (P,P)-trans-35) was prepared by McMurry coupling of (R)-3-methyl-4-keto-l,2,3,4-tetrahydrophenanthrene, which in turn was obtained through resolution or asymmetric alkylation methods.1671 X-ray analysis showed that (P,P)-trans-35 adopts a double helical structure, with the two methyl substituents in a pseudo-axial orientation. Calculations confirmed this preferred conformation for (P.P) -trans-35, and showed that (M,M)-trans-35, with both methyl groups in pseudo-equatorial orientations, was 8.6 kcal mol-1 less stable (Scheme 22). For the cis isomer, the same features were observed, with (M,M)-cis-35 (diequatorial Me-substitu-ents) less stable than (P,P)-cis-35 by 11.9 kcal mol-1. 

Zuliaurre, R., Pons, B. and Nerin, C. (1997) Speciation of trimethyllead in rainwater by gas chromatography mass spectrometry after ethylation with sodium tetraethylborate-comparison with other alkylation methods./. Chromatogr. A, 779, 299-306. 

Of course, the method is good for the allylation of the already monosub-stituted methyltetronic acid 25, which is converted into 26 and 28, as shown in Scheme 7. And since hydrogenations of the allyl chain are easily performed, the two-step combination of Pd(0)-catalyzed allylation plus hydrogenation is a convenient alkylation method, as in the formation of 21 and 29. 

Syntheses of heterocyclic compounds with perfluorinated side chains are mainly performed by substitutional fluorinations of the available fragments or by the introduction of a perfluoroalkyl group in the heterocycle. The development of convenient approaches and direct perfluoro-alkylation methods is a current challenge. 

The direct alkylation methods include the reaction of lactams with diazomethane14 and the alkylation of metal salts of lactams with alkyl halides.15 These two methods are not often used nowadays, because the alkylation can more conveniently be carried out with dialkyl sulfates or triethyloxonium fluoroborate. 

N-Alkylation methods for preparing spiro(lH-indene-l,4-piperidines) and spiro(2,3-dihydrobenzofuran-3,4-piperidines) are described (1). 

Werbel and co-workers (71) have synthesized several N-6 (88, 105-109) and some N-2 (110, 111) amino and alkyl derivatives of ellipticine (1) by straightforward alkylation methods. Paoletti and co-workers (72) have reported the synthesis of a variety of 1-amino-substituted 9-methoxyellipticines (Scheme 19) in a continuing study of the antitumor properties of these compounds. The starting 1-... 

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