Electrophilic alkyl derivatives

The pentamethyl cyclopentadiene lanthanide complexes containing hydrocarbyl substituents have been studied extensively for their applications in homogeneous catalysis and C-H activation. The well-known catalyst of the Ziegler-Nutta type Cp2LnMe(Et20) is typical of the large number of compounds [155] that have been studied. Solvent-free electrophilic alkyl derivatives serve as precursors of the majority of the compounds which have been studied. 

Meyers lactams are widely used in synthesis of substituted synthons of interest and their functionalization is carried out under strong base conditions giving C-alkyl derivatives. Alkylation of bicyclic lactam 182 with electrophiles (alkyl, allyl, benzyl halides, chlorophosphonate), and a strong base (j-BuLi, LiHMDS, or KHMDS HMDS = hexamethyldisilazide) in THF at — 78 °C gave an endo-exo mixture of products where the major one is the rro/o-compound 183 in good yields. The ratios were determined by H NMR spectroscopy and are usually up to... 

Recently, with a view to overcome the difficulty on the preparation of aryl or alkenyl halides or sulfonates, thioamides and their S-alkyl derivatives have been proposed as a new class of electrophilic partners. This palladium cross-coupling methodology was developed by Liebeskind and mostly applied to heteroaromatic templates.118 121... 

Silyl enol ethers have also been used as a trap for electrophilic radicals derived from a-haloesters [36] or perfluoroalkyl iodides [32]. They afford the a-alkylated ketones after acidic treatment of the intermediate silyl enol ethers (Scheme 19, Eq. 19a). Similarly, silyl ketene acetals are converted into o -pcriluoroalkyl esters upon treatment with per fluoro alkyl iodides [32, 47]. The Et3B/02-mediated diastereoselective trifluoromethylation [48,49] (Eq. 19b) and (ethoxycarbonyl)difluoromethylation [50,51] of lithium eno-lates derived from N-acyloxazolidinones have also been achieved. More recently, Mikami [52] succeeded in the trifluoromethylation of ketone enolates... 

Plant sterols such as stigmasterol typically contain an extra ethyl group when compared with cholesterol. Now this is not introduced by an electrophilic ethylation process instead, two successive electrophilic methylation processes occur, both involving SAM as methyl donor. Indeed, it is a methylene derivative like that just seen in ergosterol formation that can act as the alkene for further electrophilic alkylation. After proton loss, the product has a side-chain with an ethylidene substituent the side-chains of the common plant sterols stigmasterol and sitosterol are then related by repeats of the reduction and dehydrogenation processes already seen in ergosterol formation. 

Only a few reports have dealt with the behavior of tetra-azaindenes toward electrophiles, and the reactions reported involved the pyrazole ring. Thus, alkylation of 336 with alkyl halides affords a mixture of the A-alkylated derivatives 337 and 338. Compound 336 is produced by alkylation of 339. Bromination of 339 (R = H) affords the 7-bromo derivative 340 (82JHC817) (Scheme 34). Nitration of 2-methylpyrazolo[3,4-c] pyridazine occured at pyrazole C-3 (73JAP76893). Bromination of 341 with bromine in acetic acid gives 342 (83AP697). 

Alkylation of 5-amino-1,2,4-thiadiazoles (17) with methyl iodide leads to N-4 derivatives of type (18) which undergo a Dimroth rearrangement to (110) on warming in ethanol when R = H (Scheme 26). When R = methyl, phenyl, or benzyl the reaction is severly hindered <84CHEC-I(6)463>. In contrast, benzhydryl and trityl chlorides (which are harder electrophiles) alkylate (17) at the 5-amino function to give compounds of type (109) (Scheme 26). 

Hydrolytic reactions can also be applied in the synthesis of aldehydes or ketones via the corresponding 1,3-oxazine derivatives. The anion formed from 3-methyl-2-(4-pyridyl)tetrahydro-l,3-oxazine 155 on treatment with BuLi proved to react with various electrophiles (alkyl halides, carboxylic esters, acid chlorides, or aldehydes) exclusively at position 2 of the 1,3-oxazine ring and not at the pyridine nitrogen atom. The readily formed 2,2-disubstituted-l,3-oxazine... 

Whereas allyl, benzyl and propargyl electrophiles are among the most reactive towards Pd, Ni and other transition metals, ordinary alkyl halides and related alkyl electrophiles that are not /3, -unsaturated are among the least reactive carbon electrophiles with respect to oxidative addition to Pd or Ni. Most of the alkyl derivatives are also associated... 

All of the alkyl electrophiles shown in Schemes 73-78 are primary alkyl derivatives. On the other hand, cross-coupling of primary alkylzincs with secondary alkyl iodides and bromides was shown to be feasible with 4% Ni(COD)2, 8% s-Bu-Pybox (3) and DMA(N,N-Dimethylacetamide)88k (Scheme 79). More recently, a modification of this procedure through the use of -Pr-Pybox and 7 1 DMI/THF, where DMI is 1,3-dimethyl-2-imidazolidinone, in place of v-Bu-Pybox (3) and DMA has been shown to permit enantioselective alkylation of racemic secondary a-bromoamides with organozincs210 (Scheme 79). 

These compounds are more stable than the alkyl derivatives. They do not undergo thermal isomerization, and hydrolysis requires very severe conditions. The aryl cyanurates react smoothly with amines to yield 2,4,6-triamino-l,3,5-triazines. It is possible to effect electrophilic substitution of the aryl rings <59HC(l3)l,p.l7). Aryl cyanurates are hydrogenated to form cyanuric acid and the arene (equation 22) (74RTC204). 

Attention has been directed to the development of selective procedures for electrophilic alkylation of 5-alkylte-trazole derivatives with an active methylene group in the a-position at C-5. Alkylation of Schiff base 340 was effected by treating an equimolar mixture of compound 340 and an alkyl halide in THF with 1 equiv of NaHMDS (—78 °C to room temperature). The highly versatile nature of this procedure allowed a facile synthesis of monoalkylated products 341 with alkyl, allyl, and benzyl halides in good yields (Equation 61) <1998TL3367>. 

In pyrrole the a /3 reactivity ratio is much smaller than in the other 5-membered rings (see Section III,A, 2) here the formation of a relatively larger amount of 3-substituted isomer could be expected. Actually, the 5-substituted 2-alkyl derivative appears to be the main product in all the electrophilic substitutions of the 2-alkylpyrroles3 in some cases, as in the reactions with trifluoroacetic anhydride and acetyl trifluoroacetate,147 the 5-substituted isomer is apparently the only product formed. 

C o solubility increases in the similar sequence, from iodobenzene to chlorobenzene. The exception is fluorobenzene in which C6o solubility is lower than in iodobenzene. Apparently, in the case of interaction between fluorobenzene and C6o fullerene the factor of high fluorine electronegativity prevails. Moreover, as Table 3 indicates the fluorobenzene nitration gives rise to mainly para-isomer and very little ort/zo-isomers. Consequently, the entire negative charge is localized in the /jara-position in a fluorobenzene molecule. Therefore, as with Cgo solubility in alkyl derivatives of benzene (Table 2), one can anticipate that for the C6o molecule that is an electrophilic reagent, the ortho-position will be the more preferential location for electrophilic attack than the /w/ra-position. 

The examples of C6o dissolution in benzene derivatives considered in the present work evidence the clear dependence of C6o solubility on the electron density distribution in the benzene ring. We have identified a priori the electron density with the distribution of ortho-, meta-, para-isomers which form in the reactions of electrophilic substitution of the benzene derivative considered. This identification is evaluated but in some cases, such as in a series of homologs for alkyl derivatives of benzene, the total agreement between the C6o solubility and the amount of ort/io-isomers is observed (Table 2 and Fig. 7). 

The parallels between Cgo solubility in alkyl derivatives of benzene and reactivity of these derivatives to the reactions of electrophilic substitution have been established. The parallels allow the Cgo dissolution to be considered as a reaction of electrophilic substitution of aromatic hydrocarbons. 

The 1,2-dithioles (3a, b, c, d) would be expected to protonate on the exocyclic atom to generate substituted 1,2-dithiolylium salts (4) and should thus undergo electrophilic attack at this atom. Also, protons on 5-alkyl derivatives of the dithioles (3a, b, c) should be acidic because of conjugative stabilization of an anion and thus undergo typical condensation reactions, e.g. with carbonyl compounds. 

When lithium alkyl catalysts are used in non-solvating media such as aliphatic hydrocarbons, the polymer-lithium bond is not sufficiently ionic to initiate anionic polymerization so that the monomer must first complex with vacant orbitals in the lithium. A partial positive charge is induced on the monomer in the complex, and this facilitates migration of the polymer anion to the most electrophilic carbon of the complexed monomer. This type of polymerization is more appropriately termed coordinated anionic and will be discussed in the next section. There does not appear to be any evidence that alkyl derivatives of metals which are less electropositive than lithium and magnesium can initiate simple anionic polymerization. 

The only doubtful case is the secondaiy alkyl derivative, which can react by either mechanism, though it is not very good at either. The first question you should ask when faced with a new nucleophilic substitution is Is the carbon electrophile methyl, primary, secondaiy, or tertiary This will start you off on the right foot, which is why we introduced these important structural terms in Chapter 2. 

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