Alkylation direct

Treatment of the borates with iodine leads to boron- C2 migration of an alkyl group[9]. This reaction has not been widely applied synthetically but it might be more applicable for introduction of branched alkyl groups than direct alkylation of an indol-2-yllithium intermediate. 

There are a wide variety of methods for introduction of substituents at C3. Since this is the preferred site for electrophilic substitution, direct alkylation and acylation procedures are often effective. Even mild electrophiles such as alkenes with EW substituents can react at the 3-position of the indole ring. Techniques for preparation of 3-lithioindoles, usually by halogen-metal exchange, have been developed and this provides access not only to the lithium reagents but also to other organometallic reagents derived from them. The 3-position is also reactive toward electrophilic mercuration. 

Thiazolium salts can be obtained successfully by a modification of the Hantzsch s thiazole synthesis. This method is particularly valuable for those thiazolium compounds in which the substituent on the ring nitrogen cannot be introduced by direct alkylation, for example, aryl or heteroaryl thiazolium salts (Scheme 42). 

Sulfides (172) in which Rj = alkyl can be obtained also by direct alkylation of the 2-mercaptothiazoles either in alcaline medium (156, 597) or by phase-transfer catalysis in better yield (824). 

Direct alkylation of benzene using 1 chlorobutane and aluminum chloride would yield sec butylbenzene by rearrangement and so could not be used... 

Direct alkylation of esters can be carried out by forming the enolate with LDA fol lowed by addition of an alkyl halide Tetrahydrofuran (THF) is the solvent most often used m these reactions... 

Shape selective catalysts, such as ZeoHtes of the H-ZSM-5 type, are capable of directing alkyl groups preferentially to the para position (18). The ratio of the catalyst to the substrate also plays a role ia controlling the regiochemistry of the alkylations. For example, selective alkylation of anilines at the para position is achieved usiag alkylatiag ageats and AlCl ia equimolar ratio (19). 

Products do not contain 2,2,3-trimethylbutane or 2,2,3,3-tetramethylbutane, which would be expected as the primary alkylation products of direct alkylation of isobutane with propylene and isobutylene, respectively. In fact, the process iavolves alkylation of the alkenes by the carbocations produced from the isoalkanes via intermolecular hydride abstraction. 

On the other hand, under superacidic conditions, alkanes are readily alkylated via front-side CJ-iasertion by carbocationic alkylating agents. The direct alkylation of the tertiary C—H CJ-bond of isobutylene with isobutane has been demonstrated (71). The stericaHy unfavorable reaction of tert-huty fluoroantimonate with isobutane gave a Cg fraction, 2% of which was 2,2,3,3-tetramethylbutane ... 

The other important direct alkylation processes involve reaction of electron-rich olefinic compounds with either tin metal or stannous chloride (tin(II) chloride) in the presence of stoichiometric amounts of hydrogen chloride (22). Butyl acrylate (R = C Hg) was used commercially in this process to prepare the estertin or P-carboalkoxyethyltin chlorides as iHustrated in the foUowing. 

Direct alkylation or acylation of the oxygen of THF by exchange or addition occurs with the use of trialkyl oxonium salts, carboxonium salts, super-acid esters or anhydrides, acyhum salts, and sometimes carbenium salts. 

Cyclization of (68) and depiotection tfien yield the monobactam nucleus (69) which may be coupled with various C-3 side chains (48). Direct alkylation of the JV-unsubstituted azetidinone (70) using fluorotetrazole [93607-94-4], CgH FN, also produced (69) after deprotection of (71) (49). 

ButylatedPhenols and Cresols. Butylated phenols and cresols, used primarily as oxidation inhibitors and chain terrninators, are manufactured by direct alkylation of the phenol using a wide variety of conditions and acid catalysts, including sulfuric acid, -toluenesulfonic acid, and sulfonic acid ion-exchange resins (110,111). By use of a small amount of catalyst and short residence times, the first-formed, ortho-alkylated products can be made to predominate. Eor the preparation of the 2,6-substituted products, aluminum phenoxides generated in situ from the phenol being alkylated are used as catalyst. Reaction conditions are controlled to minimise formation of the thermodynamically favored 4-substituted products (see Alkylphenols). The most commonly used is -/ fZ-butylphenol [98-54-4] for manufacture of phenoHc resins. The tert-huty group leaves only two rather than three active sites for condensation with formaldehyde and thus modifies the characteristics of the resin. 

Alkylations of enamines of a,)9-unsaturated ketones with alkyl halides often give very poor yields of C-alkylated products because of competing. -alkylation.In the type of transformation illustrated here, direct alkylations of enamines are completely unsuccessful, even in cases where hindered enamines are used. On the other hand, the metaUoenamine method can be applied generally with good success in the problem of monoalkylation of ,)3-unsaturated ketones. ... 

From a synthetic point of view, direct alkylation of lithium and magnesium organometallic compounds has largely been supplanted by transition-metal-catalyzed processes. We will discuss these reactions in Chapter 8 of Part B. 

Mazur " obtained 2a-alkyl-5a-H (3) or 4 -alkyl-5 -H products (6) by direct alkylation of either 5a-H (1) or 5 -H-3-keto steroids (4) with alkyl halides under basic conditions. In general, formation and alkylation of the more stable enolate ion is observed in this procedure. 

The preparation of 17j -hydroxy-4a-methyl-5a-androstan-3-one (3) which cannot be obtained by direct alkylation or via formyl or oxalyl ketones was achieved by Schaub in 40% yield by the Stork " alkylation procedure. As discussed in the introduction this method proceeds by trapping the A -enolate (2), obtained from (1) and lithium in liquid ammonia, with methyl iodide. 

It s reasonable to ask why one would prepare a ketone by way of a keto ester (ethyl acetoacetate, for example) rather than by direct alkylation of the enolate of a ketone. One reason is that the monoalkylation of ketones via their enolates is a difficult reaction to cany out in good yield. (Remember, however, that acylation of ketone enolates as described in Section 21.4 is achieved readily.) A second reason is that the delocalized enolates of (3-keto esters, being far- less basic than ketone enolates, give a higher substitution-elimination ratio when they react with alkyl halides. This can be quite important in those syntheses in which the alkyl halide is expensive or difficult to obtain. 

One of the advantages of the enamine alkylation reaction over direct alkylation of the ketone under the influenee of strong base is that the major product is the monoalkylated derivative 29,32). When dialkylation is observed, it occurs at the least substituted carbon in contrast to alkylation with base, where the a-disubstituted product is formed. Dialkylation becomes the predominant reaction when a strong organic base is added and an excess of alkyl halide is used (29). Thus 1-N-pyrrolidino-l-cyclo-hexene (28) on treatment with two moles of allyl bromide in the presence of ethyl dicyclohexylamine (a strong organic base which is not alkylated under the reaction conditions) gave a 95 % yield of 2,6-diallylcyclohexanone (29). 

As noted above, the steroid nucleus has been a favorite for the design for site directed alkylating antitumor drugs. Thus reaction of prednisolone (62) with anhydride 63 affords the 21 acylated derivative, prednimustine (64). ... 

Sometimes ihe intermediate imine is isolated, but generally it is nol and may even be inferior to direct alkylation (5following sequence for it was desired to acetylate ihe alkylated product as formed, A solution of 50 mmol of an aromatic aldehyde (I) and 50 mmol of aminoaceialdehyde dimethylacetal (2), refluxed 1.5 h in toluene under nitrogen, gave after distillation nearly quantitative yields of the SchifTs base 3 (5d). 

Both the malonic ester synthesis and the acetoacetic ester synthesis are easy to cany out because they involve unusually acidic dicarbonyi compounds. As a result, relatively mild bases such as sodium ethoxide in ethanol as solvent can be used to prepare the necessary enolate ions. Alternatively, however, it s also possible in many cases to directly alkylate the a position of monocarbonyl compounds. A strong, stericaliy hindered base such as LDA is needed so that complete conversion to the enolate ion takes place rather than a nucleophilic addition, and a nonprotic solvent must be used. 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

A crosslinking mechanism based on these data was proposed. Initial monoalkylation at guanine is followed by a template-directed alkylation at either guanine or adenine two base pairs away on the opposite strand. In support of this, Armstrong... 

Direct alkylation of allylic alcohols via the (allyloxy)phosphonium ion intermediate normally proceeds with anti-y selectivity for the Cyclic system, and sy/i-y selectivity for the acyclic system (see Table l)35 36. 

The use of this phosphine facilitates assignment of configuration as virtual coupling is observed when the phosphines are trans (section 2.9.5).) Syntheses follow established routes using methyllithium as an alkylating agent the platinum(iV) complexes can be made by direct alkylation of platinum(IV) compounds or by oxidative addition to platinum(II) species. 

---