With Simple Alkyl Halides

10 Iwamoto, K. Shigematsu, S. Shinkai, S. Chem. Lett. 1992,1095. 

Arduini, A. Casnati, A. Dodi, L. Pochini, A. Ungaro, R. J. Chem. Soc., Chem. Commun. 1990, 

Larger alkyl groups, including butyl, octyl, and arylmethyl, have also 

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In general the Stork reaction gives moderate yields with simple alkyl halides better yields of alkylated product are obtained with more electrophilic reactants such like allylic, benzylic or propargylic halides or an a-halo ether, a-halo ester or a-halo ketone. An example is the reaction of 1-pyrrolidino-l-cyclohexene 6 with allyl bromide, followed by aqueous acidic workup, to yield 2-allylcyclohexanone ... 

Generally the desired substituted carbonyl compound 3 is obtained after hydrolytic workup under acidic conditions. With simple alkyl halides an irreversible A-alkylation may take place as a side-reaction to give a quaternary ammonium salt 7 ... 

If the potential leaving group is attached to unsaturated carbon, as in vinyl chloride or phenyl chloride, attack by nucleophiles is also extremely difficult, and these compounds are very unreactive in Sn2 reactions compared with simple alkyl halides. In these cases, the reason is not so much steric but electrostatic, in that the nucleophile is repelled by the electrons of the unsaturated system. In addition, since the halide is attached to carbon through an 5p -hybridized bond, the electrons in the bond are considerably closer to carbon than in an 5/ -hybridized bond of an alkyl halide (see Section 2.6.2). Lastly, resonance stabilization in the halide gives some double bond character to the C-Hal bond. This effectively strengthens the bond and makes it harder to break. This lack of reactivity is also tme for SnI reactions (see Section 6.2). 

The facile asymmetric synthesis of a-amino acids usually inaccessible by enzymatic processes becomes feasible by employing appropriate electrophiles such as ortho-disubstituted benzyl bromides. In the reaction with simple alkyl halides such as ethyl iodide, the use of aqueous cesium hydroxide (CsOH) as a basic phase at a lower reaction temperature is generally recommended [7e]. 

In Chapter 26 we saw that reliable C-alkylation occurs with reactive allyl halides and a halo-carbonyl compounds, but that unwanted N-alkylation often competes with simple alkyl halides. 

Indoles can be 3-alkylated by allyl alcohols in the presence of lithium perchlorate and acetic acid 101 is an example (Scheme 42). Pyrrole -alkylation can be achieved with simple alkyl halides [1-bromopentadecane, l-(bromomethyl)-, l-(3-chloropropyl)- and l-(3-iodopropyl)benzenes, 2-(2-bromoethyl)- and 2-(3-bromopropyl)naphthalenes] and mesylates [3-phenylpropyl-, l-methyl-3-phenylpropyl-, 2-(2-naphthyl)ethyl- and 3-(2-naphthyl)propyl methanesulfonates] selectively at C(2) and C(5) positions via reaction in various ionic liquids (e.g., Scheme 43) <20050L1231>. 

The anions generated from tetracaibonyl(phosphine) carbene complexes are more reactive in their reactions with organic electrophiles. This is consistent with the observation that the p/iTa of the methyl pentacarbonyl complex (88a) is increased by six orders of magnitude when one of the carbon monoxi ligands is replaced with tributylphosphine. The anion generated fr-om (106) will give good yields of alkylated products with simple alkyl halides such as ethyl bromide however, dialkylation is still a serious side reaction. It has been reported that both pentacarbonyl and tetracarbonyl(phosphine) complexes can be efficiently monoalkylated with alkyl triflates (primary and secondary). The anion (89) for example, can be monoalkyated with the 3-butenyl triflate in 80% yield. ... 

The anions generated from alkylamino carbene complexes can be alkylated in high yields with simple alkyl halides without any detectable amount of dialkylation. This is illustrated for the methyl pyiro-lidine complex (109), which can be alkylated cleanly with ethyl bromide to give the monoalkylated product (110) in 87% yield. The methyl pyrrolidine complex (109) can be prepared in nearly quantitative yield quite simply by treating an ether solution of the methyl methoxy complex (88a) with pyrrolidine at room temperature for a few minutes. A few examples of diastereoselective alkylations are known. The 0-alkylimidate carbene complex (112) can be alkylated with methyl triflate to give a 93 7 mixture of (113) and (114), which are diastereomers as a result of the chiral axis about the aza-allenyl linkage. Other examples of diastereoselective alkylations will be presented in Section 9.2.2.7. 

Although the alkylation of ammonia with simple alkyl halides does not generally afford high yields of 1° amines (Section 25.7A), this reaction using a-halo carboxylic acids does form the desired amino acids in good yields. In this case, the amino group in the product is both less basic and more sterically crowded than other 1° amines, so that a single alkylation occurs and the desired amino acid is obtained. 

Hydrogenolysis of 4-benzylpiperazine-2,6-diones over palladium-charcoal produced 4-unsubstituted piperazine-2,6-diones in high yield. The amino group in l-phenylpiperazine-2,6-dione underwent alkylation with benzyl chloride and phenacyl bromide, but not with simple alkyl halides (1638). Oxidative dimerizations of piperazine-2,6-diones in nitrobenzene have been studied (1639). 2,6-Bis(hydroxy-imino)piperazine heated with palladium-charcoal in o-dichlorobenzene gave 2,6-diaminopyrazine (465). 

At equilibrium, therefore, the Li becomes attached preferentially to the organic group best able to stabilize the negative charge. Hence, extensive exchanges and useful preparations are available from reaction of alkyl Li with aryl halides, cyclopropyl halides, alkenyl halides, alkynyl halides and a-heterosubstituted alkyl halides (including per- and polyhaloalkanes), but not with simple alkyl halides e.g., interaction of EtLi and Mel provides a mixture of EtLi and MeLi. 

Acridone is aromatised to 9-methoxyacridine, m.p. 197°C, by dimethyl sulphate under phase transfer conditions (I. Willner and M. Halpern. Synthesis, 1979. 177). Substituted acridones give mainly ff-alkyacridones on treatment with simple alkyl halides under phase transfer conditions, but branched alkyl halides favour formation of the alkoayacridine (A. Mahamoud et al. J. heterocyclic Chem., 1982, 503). 

Alkylation with simple alkyl halides is generally a poor reaction with enamines. Alkylation often takes place on nitrogen instead of carbon, and Stork and others7 have developed the aza-enolates to remedy this deficiency. A primary amine, usually cyclohexylamine, combines with an aldehyde to form an imine 42. Treatment with LDA 43 gives the lithium derivative, the analogue of a lithium enolate, known as an azaenolate 44. These intermediates are alkylated reliably at carbon 45 with most primary, and even with secondary alkyl halides, to give the alkylated aldehyde 47 after hydrolysis of the imine 46. 

The diazines react with alkyl halides to give mono-quaternary salts, though somewhat less readily than comparable pyridines. Dialkylation cannot be achieved with simple alkyl halides, however the more reactive trialkyloxonium tetrafluoroborates do convert aU three systems into di-quatemary salts. ... 

Mono-C-alkylation of pyrroles cannot be achieved by direct reaction with simple alkyl halides, either alone or with a Lewis-acid catalyst, for example pyrrole does not react with methyl iodide below 100 °C above about 150 °C, a series of reactions occurs leading to a complex mixture made up mostly of polymeric material together with some poly-methylated pyrroles. The more reactive aUyl bromide reacts with pyrrole at room temperature, but mixtures of mono- to tetra-allyl-pyrroles together with oligomers and polymers are obtained. 

Details directions for reactions of triethyl and triisopropyl phosphite with simple alkyl halides are to be found in Organic Syntheses.210... 

Although the ester 347 forms a carbanion, this fails to react with simple alkyl halides and does not incorporate deuterium when quenched with D O on the other hand, lithiated anions from 348 and 349 (the former does not form a carbanion with NaH) react with alkyl halides, apparently exclusively at the C positions... 

Alkylation. The topological analogies outlined in the previous section are substantiated further by considering the chemistry of metal dithienes. We first discuss the alkylation of anionic species. This reaction is equivalent to the alkylation of the hydroquinone dianion and aflFords members of a class of new coordination compounds (14). With simple alkyl halides the d metal dithiene dianions aflFord the 1,4-S-dialkylderiva-tives (16). With a,a>-dibromoalkanes at high dilution new chelates of type 17 were obtained for x = 5-12 (3). With smaller values of x or... 

Attack on Saturated Carbon. - Ethylene dicarboxylic diphosphonic acid (EDCP, 2) has been prepared in 70% yield from 2,3-dichlorosuccinic anhydride (3) and trimethyl phosphite, followed by hydrolysis of the Arbuzov product. Tris(trimethylsilyl) phosphite, in contrast to trialkyl phosphites, attacks an oxirane carbon of epibalohydrins (4) to give the phosphonates (5). Bis(trimethylsilyl) phosphonite (6) has previously been prepared in situ and used to obtain y-ketophosphinic acids similar reactions with simple alkyl halides to give alkylphosphinic and dialkylphosphinic acids acids in high yields have now been described. ... 

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