Ethers 1-bromoalkyl

Hydrogen bromide adds to acetylene to form vinyl bromide or ethyHdene bromide, depending on stoichiometry. The acid cleaves acycHc and cycHc ethers. It adds to the cyclopropane group by ring-opening. Additions to quinones afford bromohydroquinones. Hydrobromic acid and aldehydes can be used to introduce bromoalkyl groups into various molecules. For example, reaction with formaldehyde and an alcohol produces a bromomethyl ether. Bromomethylation of aromatic nuclei can be carried out with formaldehyde and hydrobromic acid (6). 

Figure 3.11 shows the relative reactivity as a function of ring size for two other intramolecular displacement reactions, namely, conversion of ethers from ca-bromoalkyl monoethers of 1,2-dihydroxyben-zene. 

A -( 1-Chloro- or bromoalkyl)amides are generally moisture-sensitive, unstable compounds, which are often directly used without further purification. Standard Lewis acids such as boron trifluoride-diethyl ether, aluminum(lll) chloride, zinc(II) chloride, tin(IV) chloride and titani-um(IV) chloride are used to generate the /V-acyliminium ion, although sometimes a catalyst is not necessary. 

Allenyl ethers are useful key building blocks for the synthesis of a-methylene-y-butyrolactones [129, 130], The synthesis of the antileukemic botryodiplodin was accomplished with the crucial steps briefly presented in Scheme 8.56. Bromoallenyl ethers 225 were easily prepared by base-induced isomerization from the corresponding /3-bromoalkyl alkynyl ether compounds and then subjected to electrophilic bro-mination with NBS. The resulting acetals 226 were converted into 2-alkoxy-3-methy-lenetetrahydrofurans 227 by dehydrohalogenation of the alkenyl bromide unit to an alkyne and subsequent radical cyclization employing tributyltin hydride [130],... 

Cobaloxime(I), electrochemically regenerated from chloro(pyridine)-cobaloxime (III) (232), has been employed as a mediator in the reductive cleavage of the C—Br bond of 2-bromoalkyl 2-alkynyl ethers (253), giving (254) through radical trapping ofthe internal olefin (Scheme 95) [390]. An interesting feature of the radical cyclization (253) (254) is the reaction in methanol, unlike the trialkyltin hydride-promoted radical reactions that need an aprotic nonpolar solvent. An improved procedure for the electroreductive radical cyclization of (253) has been attained by the combined use of cobaloxime(III) (232) and a zinc plate as a sacrificial anode in an undivided cell [391]. The procedure is advantageous in terms of the turnover of the catalyst and the convenience of the operation. 

A closely related reaction involves that between a saturated acyl halide and a phenol or phenolic ether. A necessary feature of the acid chloride is that it contains a bromine atom at C-2 which allows formation of a double bond during the reaction by loss of bromide. Normal Friedel-Crafts conditions are employed in the first step which leads to an o-hydroxyphenyl 2-bromoalkyl ketone (589). In boiling diethylaniline, hydrogen bromide is lost and the resulting acrylophenone spontaneously cyclizes to the chromanone <24LA(439)132). 

Treatment of 4-(2-bromoalkyl)azetidin-2-ones 205 with L1AIH4 in diethyl ether yielded 2-(l-alkoxy-2-hydroxyethyl)-azetidines 206 and small amounts (1-5%) of r-4-(2-bromoalkyl)azetidines 81 (Equation 56) <20060L1101 >. A 1,2-fission of the starting material followed by a nucleophilic substitution of bromide led toward the formation of these compounds. 1,4,4-Trisubstituted azetidin-2-ones 207 could be reduced to the corresponding azetidines 208 using lithium aluminium hydride in diethyl ether under reflux for 7-16h (Equation 57) <1996JOC6500>. 

Similar conditions were also applied with the aim to couple styrenes 44 with 2-bromoalkyl ethers or 2-bromoalkyl amines 50 and Grignard reagents (Fig. 16) [138], In contrast to alkyl halides bearing donor functionalities more remote from... 

Combining the possibility of carrying out the intramolecular carbozincation of secondary organozinc iodides with their tolerance to functional groups led the authors to consider the a-bromoalkyl acetate 57. Thus, the latter upon treatment with Zn in ether leads to 58 in moderate yields (the balance being the uncyclized material) but with a much better diastereomeric cis/trans ratio (86 14) than that obtained (58 42) via the strategy depicted in Scheme 7-39 [52] (Scheme 7-50). 

Aminoethyl ether groups were obtained by using azide as a nucleophile and subsequent reduction. Longer aminoalkyl ethers were prepared by O-alkylation with )-bromonitriles or A-((w-bromoalkyl)phthalimides followed by reduction or hydrazinolysis, respectively. 

Preparation.—The reaction of triphenylphosphine with 1-bromoalkyl ketones has been described in which the initially formed labile enolic salts (59) are converted irreversibly into phosphonium salts via ion-pairs (Scheme 4). When R is larger than ethyl the ion-pair is not formed and the enol salts decompose in the pr ence of atmospheric moisture to give alkyl aryl ketones. No enol phosphonium salts are isolated from the reaction of bromo-diketones with triphenylphosphine in ether. The phosphonium salts (60) are precipitated directly. 

Glycols HO(CH2)/iOH lose water both inter- and intramolecularly when treated with dry HBr at 80-200°, so that bis(bromoalkyl) ethers, Br(CH2) 0(CH2) Br are obtained as byproducts and also cyclic ethers when favored ring systems can be formed.906 A notable case of cyclic ether formation is that of tetrahydrofuran from 1,4-butanediol for the reverse reaction see page 237. 

For instance, 1-chloroethyl ethyl ether is obtained from acetaldehyde diethyl acetal and PC15,1057 chlorobenzyl methyl ether from benzaldehyde dimethyl acetal, acetyl chloride and SOCl21058 and 1-bromoalkyl ethers from the corresponding acetals.1059 1-Bromoalkyl ethers can also be prepared from 1-chloroalkyl ethers into which HBr is passed at about 20° 1-iodoalkyl ethers are obtained from the 1-chloro analogs by use of Nal in acetone. 

General procedure (cf. Hagemann1150) A solution of the amine in dry ether, CHC13, or benzene is added gradually to the BrCN solution (fume cupboard ). The reaction is exothermic. The mixture of amine and BrCN (1-1.1 moles per moles of amine) may also be warmed on a water-bath. By-products, mostly precipitated when a solvent is used, may contain the hydrobromide of the tertiary amine as well as the quaternary ammonium bromide (see above), the requisite HBr being liberated by olefin formation. When no solvent is used, the reaction mixture is extracted with ether. The unused amine and the salts are removed by shaking the solution of A-substituted cyanamide with dilute aqueous acid. 

The fluoro analog 463 was prepared from diethyl acetoxymalonate 458 by alkylation of its anion with benzyl-2-bromoalkyl ether to give 459, whose... 

Lithium enoiates of methyl ta-bromoalkyl ketones. House et al. us solutions of LDA in ether-hexane to generate the lithium enoiates (a) of bromo ketones. On addition of an activating ligand, particularly HMPT, the enoiates undergo intramolecular cyclization to six-membered cyclic ketones. An example is shown in equation (I). Replacement of LDA by potassium /-butoxide results mainly in formation of internal enoiates, and 2 is a minor product (14% yield). 

Bromo amines. In the presence of BF3 etherate, the reagent (1) adds to slyrene and to cyclohexene to form addition products that are reduced (NaHSOs) Id N-( -bromoalkyl)phosphoramides. These products can be transformed into i/iridines or into /3-bromo amines as shown in the formulations. Both Markov-ilkov addilion reactions are regio- and stereospecific. 

With the development of 3-(co-bromoalkyl)thiophenes, several crown ether functionalized PTs have been synthesized by Bauerle and coworkers. Electropolymerization was performed on mono-, bi-, and terthiophene monomers 65-67 substituted with pendant 12-crown-4 receptor tethered with alkyl chains [175-177]. While electropolymerization failed with 65, compounds 66, 67, and 68 were easily electro-polymerized and the chemosensing properties of the polymers were analyzed. Cyclic voltammetric analysis showed that addition of increasing amounts of Li, Na, or produces a positive shift of the oxidation potential of poly(66, n=5), while this effect is less pronounced for poly(67). On the other hand, whereas the CV of poly(68, n=5) is strongly affected by the presence of alkali ions, the lengthening of the alkyl spacer in poly(68, n = 10) produces a complete loss of ion sensitivity. Optical and spectroelectrochemical experiments revealed that the changes in electronic properties were due to hindered diffusion of the counteranions into the film during polymer oxidation [177]. 

With the development of 3-(w-bromoalkyl)thiophenes [100], several new types of crown ether functionalized PTs have been synthesized. While electropolymerization of monomeric derivatives (32) failed, probably for steric reasons, bithiophene (33) and terthiophene (34) were easily electropolymerized to the corresponding crown ether derivatized PTs [101],... 

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