Prenyl halides

Tertiary halides, acetates and methyl ethers, aryl-activated secondary halides, prenyl halides and acetates, acetals, ketals, thioacetals, a-chloroalkyl ethers, and, particularly, a-chloroalkyl phenyl sulrides have been widely used as alkylating agents. Such reagents may contain a variety of functional groups including alkenes, esters, halides, ketones, nitro groups and silyl ethers. 

Isoprene epoxidized on the vinyl group (l,2-epoxy-3-methyl-3-butene, 14) would also be an attractive synthon for monoterpenoids if it were more readily accessible. Among the possible preparative methods (Scheme 2), acid-catalyzed isomerization of 2,3-epoxy-l-halo-3-methylbutanes (epoxidized prenyl halides) and dehydrohalogenation of the resulting isomers seemed the best route until chlorination of prenyl acetate (15, R = OAc) with hypochlorous acid was published. Dehydration of the mixture of products gave a maximum of the chloroacetate 16, which yielded the epoxide 14 with sodium hydroxide in methanol. ... 

Thermolysis of the sulfone 58 gave 58% of a mixture of geraniol (25) and nerol (27) ethyl ethers. Starting from senecioic acid (59), Katzenellenbogen has continued studies of the addition of prenyl halides (15, R = halogen) to the dianion in presence of copper. Copper ion also influenced the addition of prenyl bromide (15, R = Br) to the anion of the V-methylamide of 59, its presence transforming a yield of 98% of the a-addition product to 83% of the y-product, geranic acid V-methylamide [as a mixture of (Z)- and ( )-isomers]. ... 

Prenyl ethers can be formed using the typical Williamson ether synthesis—that is, by reacting the alcohol with a suitable base and a prenyl halide. Many of the methods used for the formation of allyl and benzyl ethers should be applicable. ... 

Table 2.3 Alkylation of

An easy synthesis of prenyl naphthoquinones, e.g. menaquinone-2 (205 n = 2), was achieved by coupling the appropriate prenyl halide with an organo-copper derivative of the electrochemically derived quinone bisacetal (216). Menaquinone-2 and phylloquinone (204) were also obtained in good yields by reaction of 2-methyl-1,4-naphthoquinone (205 n =0) with geranyl and phytyl halides in the presence of metal dust. A one-step method for the preparation of vitamin K analogues uses cyclodextrin inclusion catalysts.Thus reaction of the diol (217) with allyl bromide in the presence of oxygen and/3-cyclodextrin at pH 9 afforded the menaquinone analogue (218). 

Vinylcyclopropanes.2 Allylic bromides or chlorides, particularly prenyl halides, on deprotonation with LiTMP (TMF,20°) arc converted into a carbenoid that reacts with alkencs to provide vinylcyclopropanes. 

The reaction of resorcinol with prenyl halides in ethereal solution containing alkali metals or alkaline earth metals or their hydroxides has been instanced among a range of other compounds (ref. 11). By contrast the reagent, isoprene-magnesium-diethyl ether (ref.4) with either resorcinol (R = OH,R = H) or catechol (R = H, R = OH) only afforded chroman products. 

The intramolecular insertion of an internal alkyne into an aryl or alkenyl halide 727 generates aryl- or alkenylpalladium as an intermediate, which is trapped with an organozinc or organostannane to give 728. Overall cis addition to the alkyne takes place[595,596]. The reaction of the alkenylstannane 730 with the 2-bromomethylfuran 729 is used for the introduction of a prenyl group[597]. 

With allylic Grignard reagents, the carbophilic addition on the thiocarbonyl of phenylisothiocyanate occurred as expected exclusively with inversion of the allylic chain. From crotyl and prenyl magnesium halides the compounds (4f) and (4g) were obtained in yields of 77 and 72%, respectively. 

Radical prenylotion.2 The allylstannane corresponding to 1 cannot be used for radical prenylation because of facile isomerization. However, prenylation of alkyl halides can be effected by irradiation of 1 (3 equiv.) and hexabutylditin (1.5 equiv.) Presumably 1 reacts with Bu3Sn to form an allylstannane. The yields of this process are not as high as those observed with allyltributyltin (11, 15-16). 

The alkylation goes well as 63 is the reactive allylic halide prenyl bromide and hydrolysis and decarboxylation occur as usual.13... 

If the allylic halide is unsymmetrically substituted, we can tell which process occurs and the normal result is that nucleophilic attack occurs at the less hindered end of the allylic system whether that means S 2 or Sn2. This important allylic bromide, known as prenyl bromide , normally reacts entirely via the Sn2 reaction. 

X-Substituted Allyl Anions. Allyl anions with alkyl substituents almost always react with carbonyl electrophiles at the more substituted a position, as in the reaction of the prenyl Grignard reagent with aldehydes to give the product 4.39, presumably because the metal attaches itself preferentially to the less-substituted end of the allyl system and then delivers the electrophile in a six-membered transition structure 4.38. In contrast, alkylation of a similar anion with an alkyl halide gives mainly the product 4.40 of y attack, which is normal for an X-substituted allyl anion when a cyclic transition structure is not involved. 

There has been further study of the direct prenylation of 3-methylfuran (cf. Vol. 2, p. 161, Ref. 558 Vol. 4, p. 557, Ref. 724) using 3-chloro-3-methyl-l-butene or the corresponding trifluoroacetate and zinc halides or silver tri-fluoroacetate. Rose furan was indeed obtained, but was accompanied by the 2,4-disubstituted furan. 

Silyl enol ethers also react well with allylic halides, or with the hemiterpene fragment prenyl acetate24 79 or with secondary25 80 and tertiary26 81 benzylic halides (Zn salts are used as catalysts in these examples). In each case, regioselectivity has been demonstrated with the same two isomers 22 and 25. 

This does not prevent the use of allylic bromides in synthesis. As nucleophiles may attack an allylic derivative from either end of the allylic system, there is a further opportunity to get the product with the more highly substituted double bond. You will probably know that prenylation of nucleophiles, particularly enolates, gives overwhelmingly the prenyl derivative 5. The primary allylic halide 6 (prenyl bromide) reacts by the SN2 reaction while the tertiary halide 4 reacts by the Sn2 reaction. 

---