Hydrogen bromide with ethers

In previous experiments, Bald et al. [2] had tried to liberate 131 from 3-bromo-6,7-benzobicyclo[3.2.1]octa-2,6-diene (134) by /3-elimination of hydrogen bromide with KOtBu. Both the trapping products 140 of the intermediate with DPIBF and the enol ether 138 appeared to provide evidence in favor of 131, but did not exclude the cycloalkyne 136 [94]. The generation of 136 in the presence of DPIBF by two routes that cannot lead to 131 gave rise to cycloadducts different from 140, which were converted into 140 on treatment with KOtBu, however [95, 96], On the basis of these results and further investigations [97, 98], the formation of 131 from 134 is considered unlikely. Instead of 131, 136 seems to arise and to be the source of the products observed. In contrast, the phenyl derivative 137 of 131 is the obvious intermediate in the reaction of 135 with KOtBu, which furnished the enol ether 139 [2]. 

This is manifest in the reactivity of 180/180-Z1 which was generated from 3-bromo-41-f-pyran (283) by /3-elimination of hydrogen bromide with KOtBu (Scheme 6.61). Whether or not this reaction was conducted in the presence of styrene or furan, the only product identified was tert-butyl 4H-pyran-4-yl ether (284). This is in line with the relationship of the intermediate to a pyrylium ion. Thus, the addition of the tert-butoxide ion to 180/180-Zj has to be expected at the 4-position with formation of the vinyl anion 285, which is then protonated to give 284. Likewise, the attack of the nucleophile is predicted at C2and C6 leading to the vinyl anions 286, which... 

Since the excess trimethylsilyl bromide was difficult to remove, an alternative sequence was investigated (Scheme 10). After bromination of the silyl enol ether, the reaction mixture was poured into water to hydrolyze both the trimethylsilyl bromide and the anhydride. On heating this bromoacid as before, an unexpected compound was formed. This can be rationalized as follows The reaction proceeds from the enol form, and the mechanism is formally 1,5 elimination of hydrogen bromide with concomitant loss of carbon dioxide. The second decarboxylation is analogous to the one seen earlier, and would be expected of the a,8-unsaturated ketone. 

PROBLEM 16.9 A series of dialkyl ethers was allowed to react with excess hydrogen bromide, with the following results. Identify the ether in each case. 

Following their work on the synthesis of the parent compound 2,6-naphthyridine (105) (105). Taurins and Li reported their work in full (107) and at the same time reported a synthesis of the 4-methyl derivative 104, isolated by Harkiss and Swift (62). 4-Cyano-3-pyridyl-acetonitrile (275) was methylated (CFLI-NaOQHs) in the side chain to afford 2-(4-cyano-3-pyridyl)propionitrile (276), which was treated with hydrogen bromide in ether to afford 3-amino-l-bromo-4-methyl-2,6-naphthyridine (277). Diazo-tization/bromination and replacement of the bromine groups with hydrazine gave 278, and reaction with CuS04 in acetic acid afforded 4-methyl-2,6-naphthyridine (98) (Scheme 23) (107), whose spectroscopic properties were identical with those reported previously (62,63). 

CH3OH) across the carbon-carbon double bond of crotonic acid [( )-2-butenoic acid] followed by potassium bromide treatment of the initial adduct to yield the corresponding mercuric bromide and then the formation of 2-bromo-3-methoxybutanoic acid by the addition of bromine (Br2) to the latter. Acidification to the free acid, followed by amination (NH3), formylation with the equivalent of acetic-formic anhydride, hydrogen bromide (HBr) ether cleavage, and a final pH adjustment with ammonium hydroxide produced the desired amino acid. 

FIGURE 16 4 The mechanism for the cleavage of ethers by hydrogen halides using the reac tion of diethyl ether with hydrogen bromide as an example... 

Bromoacetic acid can be prepared by the bromination of acetic acid in the presence of acetic anhydride and a trace of pyridine (55), by the HeU-VoUiard-Zelinsky bromination cataly2ed by phosphoms, and by direct bromination of acetic acid at high temperatures or with hydrogen chloride as catalyst. Other methods of preparation include treatment of chloroacetic acid with hydrobromic acid at elevated temperatures (56), oxidation of ethylene bromide with Aiming nitric acid, hydrolysis of dibromovinyl ether, and air oxidation of bromoacetylene in ethanol. 

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). 

Ethers. In the presence of anhydrous agents such as ferric chloride (88), hydrogen bromide, and acid chlorides, ethers react to form esters (see Ethers). Esters can also be prepared from ethers by an oxidative process (89). With mixed sulfonic—carboxyhc anhydrides, ethers are converted to a mixture of the corresponding carboxylate and sulfonate esters (90) ... 

The high reactivity of pyrroles to electrophiles is similar to that of arylamines and is a reflection of the mesomeric release of electrons from nitrogen to ring carbons. Reactions with electrophilic reagents may result in addition rather than substitution. Thus furan reacts with acetyl nitrate to give a 2,5-adduct (33) and in a similar fashion an adduct (34) is obtained from the reaction of ethyl vinyl ether with hydrogen bromide. 

Treatment of dibromocarbene adduct (43) (Rji, = O) with aqueous methanol containing silver nitrate or perchlorate gives A-homo-estra-1 (10), 2,4a-triene-4,17-dione (45) in 21 % overall yield from the enol ether (42). The exact pathway is not known, but the first step may be formation of a bromo-homo-dienone facilitated by the methoxyl group, which then undergoes further loss of hydrogen bromide involving shift of a double bond by enolization. ... 

Dehydrochlorination of bis(tnfluoromethylthio)acetyl chloride with calcium oxide gives bis(trifluoromethylthio)ketene [5] (equation 6) Elimination of hydrogen chloride or hydrogen bromide by means of tetrabutylammonium or potassium fluoride from vinylic chlorides or bromides leads to acetylenes or allenes [6 (equation 7) Addition of dicyclohexyl-18-crown-6 ether raises the yields of potassium fluoride-promoted elimination of hydrogen bromide from (Z)-P-bromo-p-ni-trostyrene in acetonitrile from 0 to 53-71 % In dimethyl formamide, yields increase from 28-35% to 58-68%... 

Esters of diphenylacetic acids with derivatives of ethanol-amine show mainly the antispasmodic component of the atropine complex of biologic activities. As such they find use in treatment of the resolution of various spastic conditions such as, for example, gastrointestinal spasms. The prototype in this series, adiphenine (47), is obtained by treatment of diphenyl acetyl chloride with diethylaminoethanol. A somewhat more complex basic side chain is accessible by an interesting rearrangement. Reductive amination of furfural (42) results in reduction of the heterocyclic ring as well and formation of the aminomethyltetrahydro-furan (43). Treatment of this ether with hydrogen bromide in acetic acid leads to the hydroxypiperidine (45), possibly by the intermediacy of a carbonium ion such as 44. Acylation of the alcohol with diphenylacetyl chloride gives piperidolate (46). ... 

To a solution of 30.7 g (0.203 mol) of 1-phenoxy-2-aminopropane in 150 ml of ethanol there was added 31.9 g (0.100 mol) of 1-(4 -benzyloxyphenyl)-2-bromopropanone-1. The mixture was heated to boiling temperature and the solution was then refluxed in a reflux condenser for 3 hours. Most of the ethanol was then distilled off in vacuo. Then to the residue there was added about 150 ml of diethyl ether. The hydrogen bromide salt of 1-phenoxy-2-aminopropane was filtered off and washed with diethyl ether. 

The solvents were then evaporated, y.ielding 4-[(2-methvl-1,2-dicarbobenzoxyhvdrazino)-methyl]-benzoic acid isopropylamide as a yellow oil, which crystallized upon triturating with ether MP 90°-92 C. This product was then covered with 70 ml of a 33% solution of hydrogen bromide in glacial acetic acid, and then permitted to stand for 2 hours with occas-... 

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