Bromine with enol ethers

Fluorination of an enamine, enol ether, or enol acetate with CF3OF gave 60-70% yields of fluoroketone (708). Bromination of an endiamine gave the bis-imonium salt (647). 

Yaodong Huang, while pursuing the synthesis of ( + )-berkelic acid (69), reported a diastereoselective cycloaddition using method H that leads to another type of 5,6-aryloxy spiroketals (Fig. 4.36).32 For example, addition of three equivalents of t-butyl magnesium bromide to alcohol 70 in the presence of the exocyclic enol ether 71 proceeds in a 72% yield to the spiroketal 72 with a 4.5 1 selectivity favoring the endo approach (Fig. 4.36). Additional experiments suggest the bromine atom decreases the HOMO-LUMO band gap and improves diastereoselectivity. 

Bromination rates of aliphatic enol ethers have been included in the interactive treatment of alkenes GRIC=CR R, with G being a conjugated group most of them fit the multiparameter equation (41) satisfactorily. A more detailed analysis of reactivity-selectivity effects in the reaction of 1-ethoxyethylene [22] and its a- and / -methyl analogues [23] and [24] has been carried out,... 

A synthesis of the B-ring aromatic corticosteroid (286), the analogue of cortex-olone, started with the previously reported B-ring aromatic norpregnane (285). Development of the corticosteroid side-chain employed bromination of the 17a-hydroxy-20-oxo-derivative with trimethylphenylammonium bromide perbromide. " Reaction of perchloryl fluoride with the mixed enol ethers (287) and (288) provided, after hydrolysis, the 17a-fluoro-20-oxo-compound (290) and the 21-fluoro-20-oxo-compound (291). In contrast, the enamine (289) led only to the 17a,21-difluoro-20-oxo-compound. A series of 17a-acyloxy-21-deoxy-... 

Folate analogues continue to have importance in chemotherapy, especially heterocyclic analogues other than pteridines which are covered in Chapters 10.15-10.17 and 10.19. 1,3-Dimethyllumazine analogues of folates for use as model compounds have been prepared by side-chain elaboration of 6-bromomethyl-l,3-dimethyllumazine (Scheme 34) <1996JHC341>. More notable in this work, however, was the synthesis of the bromomethyl precursor itself in addition to routine bromination of the 6-methyllumazine 175 prepared by condensation of dihydroxyacetone with 5,6-diamino-l,3-dimethyluracil, a cycloaddition reaction between trimethylsilyl enol ethers and the pyrimidyl bisimine 177, via cycloadducts such as 176, afforded substituted pteridines in moderate to good yields. 

The superfluous bromine is then removed by reduction with zinc in acetic acid (26-1). The 20 ketone is next protected against the strongly reducing conditions in the subsequent step by conversion to the ethylene glycol acetal (26-2). Birch reduction with lithium in liquid ammonia in the presence of ethanol proceeds as usual to the dihydrobenzene (26-3). Treatment of this last product with mineral acid serves to hydrolyze both the enol ether at the 3 position and the acetal at the... 

Methylene difluorocyclopropanes are relatively rare and their rearrangement chemistry has been reviewed recently [14]. In addition, electron deficient alkenes such as sesquiterpenoid methylene lactones may be competent substrates. Two crystal structures of compounds prepared in this way were reported recently [15,16]. Other relatively recent methods use dibromodifluoromethane, a relatively inexpensive and liquid precursor. Dolbier and co-workers described a simple zinc-mediated protocol [17], while Balcerzak and Jonczyk described a useful reproducible phase transfer catalysed procedure (Eq. 6) using bromo-form and dibromodifluoromethane [18]. The only problem here appears to be in separating cyclopropane products from alkene starting material (the authors recommend titration with bromine which is not particularly amenable for small scale use). Schlosser and co-workers have also described a mild ylide-based approach using dibromodifluoromethane [19] which reacts particularly well with highly nucleophilic alkenes such as enol ethers [20], and remarkably, with alkynes [21] to afford labile difluorocyclopropenes (Eq. 7). 

Bromination of the enol ether product with two equivalents of bromine followed by dehydrobromination afforded the Z-bromoenol ether (Eq. 79) which could be converted to the zinc reagent and cross-coupled with aryl halides [242]. Dehydrobromination in the presence of thiophenol followed by bromination/dehydrobromination affords an enol thioether [243]. Oxidation to the sulfone, followed by exposure to triethylamine in ether, resulted in dehydrobromination to the unstable alkynyl sulfone which could be trapped with dienes in situ. Alternatively, dehydrobromination of the sulfide in the presence of allylic alcohols results in the formation of allyl vinyl ethers which undergo Claisen rearrangements [244]. Further oxidation followed by sulfoxide elimination results in highly unsaturated trifluoromethyl ketonic products (Eq. 80). 

Another work of Duhamel and Ancel [59] related this synthesis of retinal via (3-ionylideneacetaldehyde. Condensation of methallyl-magnesium chloride with diethyl phenyl orthoformate (EtC CHOPh) led after bromination of the ene-acetal, deshydrohalogenation (NaOH 50%), ethanol elimination with hexamethyldisilazane (HMDS) and ISiMes, to the bromo-dienol ether. This latter was submitted to bromine lithium exchange and the lithio enol ether was then condensed with p ionylideneacetaldehyde to give retinal, Fig. (28). 

The most direct procedure for the synthesis of a-haloacyl silanes is electrophilic halo-genation of enolates or enol ethers of acyl silanes. This has been achieved with the silyl enol ethers using bromine at low temperatures, but the reaction suffers from the general... 

Figure 12.25 shows how acetals can be brominated electrophihcally because of the (weakly) acidic reaction conditions. Proper acidity and electrophihcity is ensured by the use of pyri-dinium tribromide (B). This reagent is produced from pyridinium hydrobromide and one equivalent of bromine. Pyridinium tribromide is acidic enough to cleave the acetal A into the enol ether G. This cleavage succeeds by way of an El elimination like the one encountered in Figure 9.32 as an enol ether synthesis. The enol ether G reacts with the tribromide ion via the bromine-containing oxocarbenium ion H and the protonated acetal D to form the finally isolated neutral bromoacetal C. (The reaction can be conducted despite the unfavorable equilibrium between the acetal A and the enol ether G, since G continuously reacts and is thus eliminated from the equilibrium.)... 

The cyclic enol ethers 76 either form 1-alkoxy furans 77 by elimination44,1 or, more interestingly, they are oxidized by bromosuccinimide to brominated intermediates 78 which give a,J3-unsaturated y-oxoesters 79 after base treatment45). Reaction of the cyclic orthoesters 76 with LiAlH4 leads to y-oxoaldehydes 80 or their acetals 81 depending on the work-up procedure 46). 

Experiments on the bromination of equilibrated ketone-acetal systems in methanol were also recently performed for substituted acetophenones (El-Alaoui, 1979 Toullec and El-Alaoui, 1979). Lyonium catalytic constants fit (57), but for most of the substituents the (fcA)m term is negligible and cannot be obtained with accuracy. However, the relative partial rates for the bromination of equilibrated ketone-acetal systems can be estimated. For a given water concentration, it was observed that the enol path is more important for 3-nitroacetophenone than for 4-methoxyacetophenone. In fact, the smaller the proportion of free ketone at equilibrium, the more the enol path is followed. From these results, it can be seen that the enol-ether path is predominant even if the acetal form is of minor importance. The proportions of the two competing routes must only depend on (i) the relative stabilities of the hydroxy-and alkyoxycarbenium ions, (ii) the relative reactivities of these two ions yielding enol and enol ether, respectively, and (iii) the ratio of alcohol and water concentrations which determines the relative concentrations of the ions at equilibrium. Since acetal formation is a dead-end in the mechanism, the amount of acetal has no bearing on the relative rates. Bromination, isotope exchange or another reaction can occur via the enol ether even in secondary and tertiary alcohols, i.e. when the acetal is not stable at all because of steric hindrance. 

You should look upon silyl enol ethers as rather reactive alkenes that combine with things like protons or bromine (Chapter 21) but do not react with aldehydes and ketones without catalysis they are much less reactive than lithium enolates. As with alkylation (p. 674), a Lewis acid catalyst is needed to get the aldol reaction to work, and a Ti(IV) compound such as TiCl4 is the most popular. 

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. 

Preussomerin I 697 and ( )-preussomerin G 698 were obtained from 620 with a five- and six-steps sequence in 15% and 12% overall yield, respectively, through modifications of substituents of the dioxocin ring. Thus, attack of lithium methoxide from the less hindered face of the enone 620, followed by protection of the phenolic oxygen as its methyl ether provided the methoxy adduct 692. The ketone 693 was obtained through a benzylic bromination-solvolysis-oxidation protocol, which required only a single purification. The C(2)-C(3) olefin was introduced by selective silylation of the C-l carbonyl of diketone 693 and oxidation of the silyl enol ether with Pd(OAc)2. Enone... 

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