A-Alky lation

As we have seen earlier in this chapter, palladium is often employed to effect A-alky-lation of indoles. Trost and Molander found that indole reacts with vinyl epoxide 415 to give indole 416 [488]. The utility of such A-alkylations remains to be established. 

A standard approach utilized for the synthesis of these C-attached AAIs involves aroylation of indole using MeMgX and ArCOCl followed by A-alky-lation using l-methyl-2-chloromethylpiperidine. The racemic compounds were then resolved either hy forming diasteromeric salts with chiral acids or by HPLC using a semi-preparative Chiracel AD column using ethanol hexane 20 80. 

A -alky lation is a common reaction of both 6-fluoro and 6-lrifluoramelhyl substituted purines. However, there are two possible outcomes N9- or A/7-alkyIalion. A study detailing the effect of the 6-substituent was reported by Geen [113] (Scheme 31). In their particular example, a 6-fluoro group (81) exerted a small influence on the A/9dV7... 

C-alkylation of secondary and tertiary aromatic amines by hexafluoroacetone or methyl trifluoropyruvate is performed under mild conditions [172] (equation 147) The reaction of phenylhydrazme with hexafluoroacetone leads selectively to the product of the C-hydroxyalkylation at the ortho position of the aromatic ring The change from the para orientation characteristic for anilines is apparently a consequence of a cyclic transition state arising from the initial N hydroxy alky lation at the primary amino group [173] (equation 148)... 

Tetralone is readily mono- or di-alkylated at the 1-position to the exclusion of O-alky lation with a range of alkylating agents under liquiddiquid two-phase conditions without an added solvent [24], Similarly, it has been reported that anthrone undergoes mono- and di-C-alky lation at the 10-position with propargyl and allyl halides to the almost complete exclusion of O-alkylation [25]. It has been claimed that methyl-ation yields 9-methoxyanthracene [26],... 

The attachment of amides to supports as A-(diarylmethyl)amides can be achieved either by acylation of resin-bound (diarylmethyl)amines, or by acid-catalyzed N-alky-lation of amides with resin-bound benzhydryl alcohols [46]. The former strategy is by far the more general. For the preparation of secondary amides RNHCOR by backbone amide linking, benzylamine linkers (Table 3.9) are more appropriate than (diary lmethyl) amine linkers, because V-al ky I - N- (di ary 1 met hy 1) amines are often difficult to acylate because of steric hindrance [242,243]. A few examples of the preparation of secondary amides by backbone amide linking to (diarylmethyl)amine linkers have been reported (Table 3.11). 

Sterically hindered p-cyano- and / -nitro-a-haloisobutyrophenones (18) have been reported to react with the 2-nitropropane anion by the S l mechanism to form the C-alky-lation product99. However, a p-nitro group is necessary for the reactions with diethyl malonate and diethyl methylmalonate, benzenethiolate and /7-toluenesulphinate ions (equation 29). 

Scheme 9.4 Problems encountered during opening of typical epoxide intermediate (see also Section 9.4, Chemical Synthesis) when intended N-external ester substituents do not bear alpha-substituents [10]. A Normal, well-behaved reaction as typically deployed for beta-blockers wherein the N-alkyl group bears an alpha-substituent as most commonly represented by isopropylamine. B The over-alky-lation problem that occurs significantly when the N-alkyl group is not alpha-substituted. Also note that when n = 3 or 4, the first alkylation is instead followed immediately by an intramolecular ring-closure reaction to form the five- or six-membered lactam. These unwanted side products, although readily...

This regiocontrol permits a tandem alky lation-Diels-Alder addition (equation I). 

Hydrogen Transfer. Hydrogen transfer (sometimes called self alky-lation of isobutane) occurs with propylene-isobutane mixtures using HF catalyst. This is a chain initiative reaction in that tertiary butyl carbo-nium ions are formed. End products are (I) propxine and (2) 2,2,4-trimethylpientane. Reactions follow ... 

Methanesulfonic acid is too powerful a catalyst for 0-alky lation with the vinyl ether, causing explosive polymerisation of the latter on multimolar scale. Dichloroacetic acid is a satisfactory catalyst on the 3 g mol scale. 

Syn-proximal di[(2-pyridylmethyl)oxy]calix[4]arene 3a has proved to be a useful achiral intermediate for the production of inherently chiral derivatives, and some chemical modifications are shown in Scheme 3. Dissolution of 3a in Mel at room temperature produces the chiral IV-methylpyridinium derivative 8 in a nearly quantitative yield [18], while MCPBA oxidation in diethyl ether has led to the isolation of the chiral mono-A-oxide 9 [53]. The reluctance of 8 to undergo further IV-alky lation suggests the hypothesis that the lone pair of the residual ring nitrogen is... 

Alkynes can also be hydroformylated, but hydrogenations of the starting materials or of the resulting olefinic products can not usually be suppressed. If one succeeds, however, to trap the primarily formed a,/ -unsaturated aldehydes intra-molecularly, preparatively useful transformations can be achieved for example, from -alky-nyl amines 44 one can obtain pyrroles 46 in good yields [19]. It is questionable whether the intermediate 45 is formed, since usually hydroformy-lation is a stereospecific cis addition (cf. Scheme 1), so that in this case an isomerization has to have taken place (Scheme 6). Recently, the hydrofor-mylation of non-terminal alkynes 47 was achieved for the first time in good yields leading... 

Dichloro-s-triazine and its 6-alky] analogs are as easily hydrolyzed by water as trichloro-a-triazine and, on suspension in aqueous ammonia (26°, 16 hr), the first is diaminated in good yield. 2,4-Bistrichloromethyl-6-methyl- and -6-phenyl- -triazines (321) require a special procedure for mono-alkoxylation (0-20°, 16 hr, alcoholic triethylamine) disubstitution occurs at refiux temperature (8 hr). Aqueous triethylamine (100°, 3 hr) causes complete hydroxy-lation of 2,4,6-tris-trichloromethyl-a-triazine which can be mono-substituted with ammonia, methylamine, or phenoxide ion at 20°. 

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