Alkyl bromides, reaction with sodium

Acyl carbonyl ferrates are involved as intermediates in two preparations of aldehydes. Alkyl bromides react with sodium tetracarbonyl ferrate(—ii) (from iron pentacarbonyl and sodium) by a process of oxidative addition to furnish the ferrate(—i) (124) this species rearranges on treatment with triphenylphosphine to a phosphonium-substituted acyl ferrate(—i) (125), which is subsequently cleaved by acetic acid to the homologous aldehyde, as outlined in Scheme 46. A related procedure employs reaction of an acid halide with sodium tetracarbonyl ferrate(—ii) to afford the acyl ferrate(—i) (126) directly this species is also cleaved by acetic acid, and affords yet another method for the reduction of acid halides to aldehydes. 

Thus, the reaction of alkyl halides and a-halo esters with sodium nitrite provides a very useful synthetic method for nitroalkanes and a-nitro esters. However, ethyl bromoacetate is exceptional in that it fails to give ethyl nitroacetate on treatment with sodium nitrite.93 This is due to the acidic hydrogen of the ethyl nitroacetate, which undergoes a further reaction with sodium nitrite to give the oxidized products (see Section 6.1, which discusses the Nef reaction). In a similar way, the reaction of benzyl bromide with sodium nitrite at 25 °C gives benzoic acid predominantly. To get phenylnitromethane, the reaction must be carried out at low temperature (-16 °C) (Eq. 2.48).93... 

The key intermediate 124 was prepared starting with tryptophyl bromide alkylation of 3-acetylpyridine, to give 128 in 95% yield (Fig. 37) [87]. Reduction of 128 with sodium dithionite under buffered (sodium bicarbonate) conditions lead to dihydropyridine 129, which could be cyclized to 130 upon treatment with methanolic HC1. Alternatively, 128 could be converted directly to 130 by sodium dithionite if the sodium bicarbonate was omitted. Oxidation with palladium on carbon produced pyridinium salt 131, which could then be reduced to 124 (as a mixture of isomers) upon reaction with sodium boro-hydride. Alternatively, direct reduction of 128 with sodium borohydride gave a mixture of compounds, from which cyclized derivative 132 could be isolated in 30% yield after column chromatography [88]. Reduction of 132 with lithium tri-f-butoxyaluminum hydride then gave 124 (once again as a mixture of isomers) in 90% yield. 

The synthesis of zolpidem began with an alkylation/condensation reaction of amino-pyridine 5 and bromide 6 to give imidazopyridine 7 (Scheme 15.1). Mannich-type reaction with formaldehyde and dimethylamine provided 8. Treatment of 8 with methyliodide to form the quaternary salt 9, followed by reaction with sodium cyanide, gave 10. Acidic hydrolysis followed by reaction of the resultant acid 11 with carbonyldiimidazole (GDI) and dimethylamine afforded zolpidem (1) in 46% overall yield (George et al., 1991 Rossey and Long, 1988). 

The seemingly complex imidazolone (78-3) is in fact obtained in a single step by reaction of the amino-ester (78-1) with the iminoether (78-2) derived from capro-nitrile. The relatively acidic proton on the heterocyclic ring is next removed by reaction with sodium hydride. This anion is then alkylated with the same biphenyl-methyl bromide (77-2) that was used to prepare losartan to afford (78-4). The nitrile group is in this case converted to the tetrazole by means of tributyltin azide, a reagent that involves milder conditions than the traditional acidic medium used to generate hydrazoic acid. Thus, treatment of (78-4) with the tin reagent affords irbesartan (75-5) [82]. 

The 2,3-dihydrobenzo[6]selenophene (113) yields the oxide (114) on treatment with ozone. The oxide may be ring opened by treatment with sodium hydride and the product of the ring opening can be alkylated by reaction with benzyl bromide. Thermal rearrangement of the oxide yields a 15 85 mixture of compounds (115) and (116) (Scheme 15) (76JOC2503). 

The ready replacement of the halogen in an alkyl or an aralkyl halide illustrated in Expt 5.157 by reaction with sodium or potassium cyanide is inapplicable in the case of aryl halides wherein the halogen is relatively inert. However, aryl bromides can be converted into nitriles in good yield by heating them for several hours at about 200 °C with copper(i) cyanide in the presence of pyridine (e.g. 1-naphthonitrile, Expt 6.168). This displacement may be achieved more readily by using dimethylformamide as the solvent, when reaction is usually completed in a few hours at reflux temperature.63... 

Acetate functional groups are quite prevalent in insect sex pheromones and have been introduced into a wide variety of alkyl bromides by reaction with sodium acetate in DMF372 or acetic acid371. As is generally the case, the use of PTC allows reaction under milder conditions and significantly improves yields and reduces reaction times. In one example the reaction of alkyl halides with formate anion has given excellent yields of a variety of alkyl formates212. 

Alkylation of 2-substituted quinazolin-4(3//)-ones by reaction with sodium hydride in dimethylformamide followed by alkylation provided O-and N-alkyl derivatives. The extent of alkylation at the different sites was reasonably explained in terms of steric properties of the 2-substituents. The silver salt of quinazolin-4(3H)-one and tetra-0-acetyl-) -D-glucopyrano-syl bromide gave a 40% yield of the 0-glycosyl derivative in contrast with the mercury salt, which gave mainly the iV-3-glycosyl derivative. As in the alkylation of mercapto compounds, quinazoline-4(3H)-thione gave the S-glycosyl derivative. If sodium hydroxide was used as base a 56% yield of the... 

Reissert compounds of the type 33 (n = 330,49 and 430) undergo an intramolecular alkylation on treatment with sodium hydride in dimethyl-formamide to give the tricyclic compounds (34). A similar reaction also takes place in the quinoline series.30 When 33 (n = 3) and isopropyl bromide are treated with sodium hydride, cyclization to 34 (n = 3) takes place rather than alkylation with the isopropyl bromide however, treatment of 33(n = 3) and carbon disulfide-methyl iodide with sodium hydride gives 35 rather than cyclization.30 Alkaline peroxide converts the nitrile 34 (n = 3) into an amide, and acid or base hydrolysis gives 4-(l-isoquinolyl)butyric acid.30... 

The second classical reaction mentioned above is the acetoacetic ester synthesis. this reaction, an ester of acetoacetic acid (3-oxobutanoic acid) such as ethyl acetoacetate is treated with base under thermodynamic control conditions and alkylated, as with the malonic ester synthesis. Reaction with sodium ethoxide in ethanol (since an ethyl ester is being used) generated the enolate and quenching with benzyl bromide led to 84. Saponification and decarboxylation (as above) gave a substituted ketone (85). Although the malonic ester synthesis and the acetoacetic ester synthesis are fundamentally similar, the different substrates lead to formation of either a highly substituted acid or a ketone. The reaction is not restricted to acetoacetate derivatives, and any p-keto-ester can be used (ethyl 3-oxopentanoate for example). ... 

The insolubility of some salts in organic solvents can be used to drive an equilibrium in the direction required. For example, in the synthesis of this alkyl iodide from the alkyl bromide by reaction with sodium iodide, acetone is used as the solvent. Why Well, sodium iodide is rather more soluble in acetone than is sodium bromide so as sodium bromide is removed from the equilibrium mixture, more of the starting materials have to convert to the products to restore the equilibrium constant. You will meet more on this reaction in Chapter 15. 

Primary alkyl chlorides and bromides can be distinguished from aryl and alkenyl halides by reaction with sodium iodide in acetone (Finkelstein reaction) ... 

The following alkyl bromide gives both cis- and fr ns-2-butene upon reaction with sodium ethoxide. Only one of these alkenes retains the deuterium label. Draw both products and explain why only one is deuterated. 

The products of the reaction of radical anions, for example sodium naphthalene, with bromides and chlorides are the hydrocarbon, the olefin and alkylated dihydronaphthalene. Reaction with iodides gives hydrocarbon dimer in addition.The mechanism as shown is a result of numerous product and kinetic studies (2 4, 5). Two steps that merit further investigation are the... 

Iodides can be made smoothly from tosylates or bromides by reaction with sodium iodide in acetone.There are also several procedures based on phosphorus reagents which are mechanistically related to those discussed for bromides and chloride. One procedure involves preparation of a cyclic phosphite ester from the alcohol and c -phenylenephosphorochloridite. Treatment of the cyclic phosphite with iodine then generates the alkyl iodide.An alkoxyphosphonium intermediate is involved. 

Alkvl Azides from Alkyl Bromides and Sodium Azide General procedure for the synthesis of alkyl azides. In a typical experiment, benzyl bromide (360 mg, 2.1 mmol) in petroleum ether (3 mL) and sodium azide (180 mg, 2.76 mmol) in water (3 mL) are admixed in a round-bottomed flask. To this stirred solution, pillared clay (100 mg) is added and the reaction mixture is refluxed with constant stirring at 90-100 C until all the starting material is consumed, as obsen/ed by thin layer chromatographv using pure hexane as solvent. The reaction is quenched with water and the product extracted into ether. The ether extracts are washed with water and the organic layer dried over sodium sulfate. The removal of solvent under reduced pressure affords the pure alkyl azides as confirmed by the spectral analysis. ... 

Iodide ion (I ) Alkyl chlorides and bromides are converted to alkyl iodides by treatment with sodium iodide in acetone Nal is soluble in acetone but NaCI and NaBr are insoluble and crystallize from the reaction mixture making the reac tion irreversible... 

Substitution can take place by the S l or the 8 2 mechanism elimination by El or E2 How can we predict whether substitution or elimination will be the principal reac tion observed with a particular combination of reactants The two most important fac tors are the structure of the alkyl halide and the basicity of the anion It is useful to approach the question from the premise that the characteristic reaction of alkyl halides with Lewis bases is elimination and that substitution predominates only under certain special circumstances In a typical reaction a typical secondary alkyl halide such as iso propyl bromide reacts with a typical Lewis base such as sodium ethoxide mainly by elimination... 

Both reactants m the Williamson ether synthesis usually originate m alcohol pre cursors Sodium and potassium alkoxides are prepared by reaction of an alcohol with the appropriate metal and alkyl halides are most commonly made from alcohols by reaction with a hydrogen halide (Section 4 7) thionyl chloride (Section 4 13) or phosphorus tri bromide (Section 4 13) Alternatively alkyl p toluenesulfonates may be used m place of alkyl halides alkyl p toluenesulfonates are also prepared from alcohols as their imme diate precursors (Section 8 14)... 

The reactions of trialkylboranes with bromine and iodine are gready accelerated by bases. The use of sodium methoxide in methanol gives good yields of the corresponding alkyl bromides or iodides. AH three primary alkyl groups are utilized in the bromination reaction and only two in the iodination reaction. Secondary groups are less reactive and the yields are lower. Both Br and I reactions proceed with predominant inversion of configuration thus, for example, tri( X(9-2-norbomyl)borane yields >75% endo product (237,238). In contrast, the dark reaction of bromine with tri( X(9-2-norbomyl)borane yields cleanly X(9-2-norbomyl bromide (239). Consequentiy, the dark bromination complements the base-induced bromination. 

Reaction conditions depend on the reactants and usually involve acid or base catalysis. Examples of X include sulfate, acid sulfate, alkane- or arenesulfonate, chloride, bromide, hydroxyl, alkoxide, perchlorate, etc. RX can also be an alkyl orthoformate or alkyl carboxylate. The reaction of cycHc alkylating agents, eg, epoxides and a2iridines, with sodium or potassium salts of alkyl hydroperoxides also promotes formation of dialkyl peroxides (44,66). Olefinic alkylating agents include acycHc and cycHc olefinic hydrocarbons, vinyl and isopropenyl ethers, enamines, A[-vinylamides, vinyl sulfonates, divinyl sulfone, and a, P-unsaturated compounds, eg, methyl acrylate, mesityl oxide, acrylamide, and acrylonitrile (44,66). 

Etherification. The reaction of alkyl haUdes with sugar polyols in the presence of aqueous alkaline reagents generally results in partial etherification. Thus, a tetraaHyl ether is formed on reaction of D-mannitol with aHyl bromide in the presence of 20% sodium hydroxide at 75°C (124). Treatment of this partial ether with metallic sodium to form an alcoholate, followed by reaction with additional aHyl bromide, leads to hexaaHyl D-mannitol (125). Complete methylation of D-mannitol occurs, however, by the action of dimethyl sulfate and sodium hydroxide (126). A mixture of tetra- and pentabutyloxymethyl ethers of D-mannitol results from the action of butyl chloromethyl ether (127). Completely substituted trimethylsilyl derivatives of polyols, distillable in vacuo, are prepared by interaction with trim ethyl chi oro s il an e in the presence of pyridine (128). Hexavinylmannitol is obtained from D-mannitol and acetylene at 25.31 MPa (250 atm) and 160°C (129). 

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