Allylic bromide intramolecular reaction

Organoboranes are reactive compounds for cross-coupling[277]. The synthesis of humulene (83) by the intramolecular cross-coupling of allylic bromide with alkenylborane is an example[278]. The reaction of vinyiborane with vinyl-oxirane (425) affords the homoallylic alcohol 426 by 1,2-addition as main products and the allylic alcohol 427 by 1,4-addition as a minor product[279]. Two phenyl groups in sodium tetraphenylborate (428) are used for the coupling with allylic acetate[280] or allyl chloride[33,28l]. 

Perfluoronaphthalene undergoes an intermolecular substitution followed by intramolecular cyclLzation on reaction with allyl bromide and mercaptide ion to furnish a dihydrothiophene denvative in high yield [34] (equation 23). 

The indium-mediated allylation of trifluoroacetaldehyde hydrate (R = H) or trifluoroacetaldehyde ethyl hemiacetal (R = Et) with an allyl bromide in water yielded a-trifluoromethylated alcohols (Eq. 8.56).135 Lanthanide triflate-promoted indium-mediated allylation of aminoaldehyde in aqueous media generated (i-airiinoalcohols stereoselectively.136 Indium-mediated intramolecular carbocyclization in aqueous media generated fused a-methylene-y-butyrolactones (Eq. 8.57).137 Forsythe and co-workers applied the indium-mediated allylation in the synthesis of an advanced intermediate for azaspiracids (Eq. 8.58).138 Other potentially reactive functionalities such as azide, enone, and ketone did not compete with aldehyde for the reaction with the in situ-generated organo-indium intermediate. 

The same coordination is used to account for the observed anti preference in the allylation of (t-hydroxybutanal with allyl bromide/indium in water (Scheme 8.16). The intermediate leads to the anti product. In support of the intramolecular chelation model, it is found that if the hydroxy group is converted to the corresponding benzyl or t-butyldimethylsilyl ether, the reaction is not stereoselective at all and gives nearly equal amounts of syn and anti products. 

Diterpenoids related to lambertianic acid were prepared by intramolecular cyclization of either an alkene or an alkyne with a furan ring <2005RJ01145>. On heating amine 101 with allyl bromide, the intermediate ammonium ion 102 was formed which then underwent [4+2] cycloadditions in situ to give the spiroazonium bromides 103 and 104 (Scheme 13). These isomers arose from either endo- or co-transition states. The analogous reaction was also carried out with the same amine 101 and propargyl bromide. The products 105 and 106 contain an additional double bond and were isolated in 58% yield. The product ratios of 103 104 and 105 106 were not presented. 

Double alkylation of ( + )-(3/ )-ll [ ]d6 25.9 (c = 0.61, CHC13) ca. 93% ee with the dibromo compound 14, i.e., first an intermolecular alkylation by an allylic bromide, followed by an intramolecular alkylation with a homoallylic bromide, yielded (-)-15 in 54% yield and with very high diastereoselectivity60. The reaction is carried out in one pot with addition of the base, in this case potassium hexamethyldisilazanide (KHMDS), in two portions. 

The reaction of methyl ester of D-alanine 185 with 4-methoxy-2-nitrobenzenesulfonyl chloride 186 in presence of ethyl diisopropylamine gave the sulfonamide 187, which was alkylated with allyl bromide 188 to afford 189 (Scheme 41). Ozonolysis of 189 resulted in the formation of aldehyde 190, and the subsequent reductive cyclization with zinc and AcOH led to the benzothiadiazepine 120 through intramolecular reductive alkylation. Using similar reaction sequence, the 1,2,5-thiadiazepines 191 and 192 were also synthesized <2003JME1811>. 

Alkyl halides (particularly bromides) undergo oxidative addition with activated copper powder, prepared from Cu(I) salts with lithium naphthalenide, to give alkylcopper species10. The alkyl halides may be functionalized with ester, nitrile and chloro functions ketone and epoxide functions may also be tolerated in some cases11. The resulting alkylcopper species have been shown to react efficiently with acid chlorides, enones (conjugate addition) and (less efficiently) with primary alkyl iodides and allylic and benzylic bromides (equations 5 and 6). If a suitable ring size can be made, intramolecular reactions with epoxides and ketones are realized. 

Highly enantioselective Rh-catalyzed intramolecular Alder-ene reactions for the synthesis of chiral 3-alkylidene-4-vinyltetrahydrofurans were reported by Zhang, as illustrated below <02AG(E)3457>. Metallic indium was also shown to mediate the intramolecular cyclization of tethered allyl bromides onto terminal alkynes to afford 3-methylene-4-vinyltetrahydrofurans in 50-62% yield <02SL2068>. 

The intramolecular cyclization of tethered allyl bromides onto terminal alkynes mediated by metallic indium proceeds smoothly and cleanly in a mixture of THF and water to give unsaturated carbocycles and heterocycles in good yields. The reaction does not proceed efficiently under rigorously anhydrous conditions (Scheme 72). 

We shall end this section with a beautiful illustration of an intramolecular 1,3-dipolar cycloaddition of a nitrile oxide that was used in the synthesis ofthe vitamin biotin. Starting at the beginning of the synthesis will allow you to revise some reactions from earlier chapters. The starting material is a simple cyclic allylic bromide that undergoes an efficient 5 2 reaction with a sulfur nucleophile. In fact, we don t know (or care ) whether this is an 5 2 or S 2 reaction as the product of both reactions is the same. This sort of chemistry was discussed in Chapter 23 if you need to check up on it. Notice that it is the sulfur atom that does the attack—it is the soft end of the nucleophile and better at Sn2 reactions. The next step is the hydrolysis ofthe ester group to reveal the thiolate anion. 

Diastereoselective macrocycUzation. A ke> step in a synthesis of the 14-membered cembranoid asperdiol (4) involves intramolecular ( yclization of the aldehydo allylic bromide (1) with chromium(II) chloride. The intermolccular version of this reaction is known to be anf/-selective (8,112). Treatment of racemic 1 with CrCl, (5 equiv., THF) results in a 4 1 mixture of the two anti-diastereomers 2 and 3 in 64% combined yield. The stereochemistry of this cyclization is evidently controlled by the remote epoxide group. The natural product was obtained by deprotection of 2 (Na/NH, 51% yield). 

Once the strategy was selected, the validation of the relevant cyclization in solution and the determination of its stereochemical outcome and yield were carried out. The synthetic scheme is reported in Fig. 3.6. The commercially available allyl (3.3) and propargylglycines (3.7) were sequentially tosylated and alkylated with propargyl and allyl bromide, respectively, to give 3.5 and 3.9. The intramolecular Pauson-Khand cyclization produced the two isomers 3.6 and 3.10, with different stereochemistries, in a stereospecific reaction (the chiral allylglycine produced 3.6 as a single enantiomer. 

In essence, the ideology of this synthesis is similar to that employed in the Robinson annulation. In fact, here again the carbanionic intermediate 99 (formed upon the initial addition of arylmagnesium cuprate reagent 100 at the double bond of Michael acceptor 98) is treated with a carbon electrophile (allyl bromide) to give the final adduct 97 with two new C-C bonds. The only essential difference lies in the fact that the quenching of the enolate intermediate 99 with the electrophile occurs as an intermolecular reaction (in contrast to the Robinson annulation where this step proceeds intramolecularly). 

Rearrangement processes of alkyltitanocene dichlorides that occur under electron impact have been investigated using deuterium labelling. A novel type of zirconium-mediated coupling reaction of alkynes with vinyl bromide to afford 2,3-disubstituted dienes has been reported (see Scheme 105), and an inter-intramolecular reaction sequence has been proposed for the observed formation of vinylcyclohexadienes and/or methylenecycloheptadienes from the copper-catalysed reaction of zirconacyclo-pentadienes with allylic dichlorides. The essential step in these processes appears to be transmetallation of the zirconium-carbon bond of the zirconacyclopentadiene to produce a more reactive copper-carbon bond. New phosphorus heterocycles, e.g. (417), have been constructed by the thermal rearrangement of a [l,4-bis(trimethylsilyl)->/ -cyclooctatetraene]- ,3,5-triphospha-7-hafhanorbomadiene complex (416). 

Such a procedure has been exploited for the synthesis of several derivatives for which an anti-inflammatory activity has been claimed [58]. A derivative under study as the Histamine H3 antagonist was prepared by the thermal intramolecular Diels-Alder reaction of a triene derivative of buta-1,3-diene-1-sulfonic acid amide. 1,3-Butadiene sulfonamides 182 (a 67%, b 69%, c 99%, d 51%) were prepared by the base mediated condensation of M-Boc-methanesulfonamides (181) with a series of aldheydes. N-akylation of 182 to give trienes 183 (a 69%, b 76%, c 82%, d 59%) was achieved by reacting the sodium salts with allyl bromide in THF at reflux. The intramolecular Diels-Alder reactions of compounds 183 were performed at 145 °C in toluene in a sealed vessel under argon. Under these conditions compounds 184 and 184 were obtained in good yields (a 76% ratio 6 1, b 71% ratio 6 1, c 92% ratio 3 1, d 87% ratio 3 1). 

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