Halocyclization

The asymmetric halocyclization reaction represents one of the most important transformations [43] in the construction of enantioenriched heterocycles containing 

Denmark and Burk s work X = O, with PhjP = S as cocatalyst, R = aryl, 

SCHEME 2.32 Phosphoric acid-catalyzed asymmetric bromocycloetherification reaction. 

SCHEME 2.33 Phosphoric acid-catalyzed intermolecular bromoesterification reaction of carboxylic acids. 

In general, cyclization can be expected in compounds having the potential for formation of five- or six-membered rings. In addition to the more typical bromination reagents, such as those listed in Table 4.2, the combination of trimethylsilyl bromide, a tertiary amine, and DMSO can effect bromolactonization. 

Electrophilic Additions to Carbon-Carbon Multiple Bonds 

3-Phenylprop-2-enyl sulfates are cyclized stereospecifically and with Markovnikov regiochemical control. These are endo-6 cyclizations. 

Iodine is a very good electrophile for effecting intramolecular nucleophilic addition to alkenes, as exemplified by the iodolactonization reaction71 Reaction of iodine with carboxylic acids having carbon-carbon double bonds placed to permit intramolecular reaction results in formation of iodolactones. The reaction shows a preference for formation of five- over six-membered72 rings and is a stereospecific anti addition when carried out under basic conditions. 

Under kinetic conditions, iodolactonization reflects reactant conformation. Several cases illustrate how the stereoselectivity of iodolactonization can be related to reactant conformation. For example, the high stereoselectivity of 1 corresponds to proximity of the carboxylate group to one of the two double bonds in the preferred reactant 

---

Halocyclization of 8-(allylamino)quinolines 408 with I2 afforded 3-iodomethyl-2,3-dihydro-l//-pyrido[l,2,3-[Pg.318]

Examples of halolactonization and related halocyclizations can be found in Scheme 4.4. The first entry, which involves NBS as the electrophile, demonstrates the anti stereospecificity of the reaction, as well as the preference for five-membered rings. 

Figure 1. Generalized scheme for halocyclization of a 1, oo-alkenol or l,co-alkenoic acid, R=0, H2, n=l-3.

Table 3. Enantiomeric excesses obtained from halocyclizations of various l,o-alkenols or l,co-alkenoic acids with halonium ions of dimeric hydroquinidine or dimeric hydroquinine species 14,15,16. ... 

Very recently, Ishirihara et al. [237] reported the application of a chiral iodine atom throngh the reaction of NSI and a chiral nucleophilic phosphoramidite for the halocyclization of homo(polyprenyl)arenes. 

Systems which can react by either 5-exo or 6-endo cyclization normally produce the five-membered ring system. Exceptions result when equilibration of the initially formed five-membered ring is facile and substitution electronically favors the 6-endo mode of cyclization. Several examples have been found in amidoselenation reactions.41158 216 216 232 For example, halocyclization of thioimidate (17) produced only the pyrrolidone product,217b 217c 233 while selenocyclization of amide (18) produced only the piperi-done product.232 Note that the cyclization of (18) to a piperidone also involves regioselectivity in the cyclization of an amide functionality to a lactam rather than an imidate. Both the ring size and type of product can be explained by equilibration. 

A recent paper276 has shown that some halocyclizations involving sulfur functionalities other than thiols (e.g. thiazolidinones) may involve initial reaction at sulfur to generate a sulfenyl halide which cy-clizes via attack of the electrophilic sulfur. This type of reaction would be an alternative to the nucleophilic heterocyclization mechanism previously proposed for a synthesis of a biotin intermediate from a vinylthiazolidine. P 277... 

The halocyclization of unsaturated benzyl sulfides is influenced by the degree of unsaturation. Thus alkenyl sulfides yield tetrahydrothiopyrans through (y-endo-trig and (y-exo-trig modes (Equation 141), whereas alkynyl sulfides afford 2-methylenetetrahydrothiopyrans by a 6-exo-dig cyclization (Equation 142) <1995JOC6468>. 

Transfer of a halonium ion to l,o)-alkenols or l,co-alkenoic acids which are capable of undergoing halocyclization is a key method to generate 4-, 5- and 6-membered heterocyclic rings via the so-called halocyclization processes 1,2,3,4,5,6,7). This synthetic method would be far more valuable if the halogen transfer to an achiral alkene could be conducted in a chiral fashion (exemplified in Figure 1) as it would produce optically active heterocycles that could be further functionalized through manipulation of the halomethyl group. 

Thermodynamic control of the lactonization can be achieved by reaction of unsaturated carboxylic acids with iodine in acetonitrile in the absence of a base19. The halocyclization occurs in high yield and selectivity via the protonated lactone that affords the more stable isomer. Under these conditions 3-substituted 4-alkenoic acids 10 and 4-substituted 5-alkenoic acids (e.g., 12) give the Y/ .v-isomer with very high stereoselectivity. 

The important role played by the conditions of the halocyclization, and by the halogen employed, is evident in the cyclization of 2-hydroxy-6-[( )-l-propcnyl]cyclohexanecarboxylic acid (5), a precursor in the total synthesis of ( )-ramulosin2. When the iodolactonization is conducted with iodine and potassium iodide in aqueous sodium hydrogen carbonate, a mixture of 6/7/8 (X = 1) in a 14 57 29 ratio is obtained in 91 % yield, whereas a mixture of 6/7 in a 60 40 ratio and 86% yield is observed when the reaction is performed with iodine in diethyl ether/tetrahy-drofuran/aqueous sodium hydrogen carbonate. By contrast, the bromolactonizalion, carried out with bromine in methanol6, affords a 78 22 mixture of 6 and 7 (X = Br) in 88% yield. 

The halocyclization of ( )-2-methyl-3-pentenoic acid occurs with high stereoselectivity under various conditions affording the y-iodo- and y-bromolactones20. (/ )-( )-2-Methyl-3-pentenoic acid (5), easily obtained by separation of the racemic acid with (R)- or (S)-a-methylbenzyl-amine, affords the (37 ,47 ,5,S )-y-lactone 6 susceptible to further transformation. The iodolac-tonc is obtained in 95% yield by reaction of the sodium salt of the unsaturated acid with iodine in methanol/water (85 15) containing sodium hydrogen carbonate at — 78 °C for 6 h. The IR spectrum confirms the presence of the y-lactone functionality while the H-NMR data is consistent with a trans,trans-arrangement21 of the substituents. The bromolactone can be obtained in 85-90% yield (mp 45-46°C) by treatment of the thallium salt of (E)-5 with bromine in dichloromethane at — 78 °C20. 

---