5-Hexenyl halides

Radical cyclization of polyfunctional 5-hexenyl halides mediated by Et2Zn and catalyzed by nickel or palladium salts has been demonstrated to produce stereoselectively polyfunctional 5-membered carbo- and heterocycles [56, 57]. Based on this strategy a formal synthesis of methylenolactocin (11) was achieved (Scheme 20). The acetal 130, readily being built up by asymmetric alkylation of aldehyde 127 followed by reaction with butyl vinyl ether and NBS, served as the key intermediate for the construction of the lactone ring. Nickel(II)-catalyzed carbometallation was initiated with diethylzinc to yield exclusively the frans-disubstituted lactol 132, which could be oxidized directly by air to 134. Final oxidation under more forcing conditions then yielded the lactone (-)-75 as a known intermediate in the synthesis of (-)-methylenolactocin (11) [47aj. 

Garst and coworkers have used the reactions of l-methyl-5-hexenyl halides 136, (X = Hal) with alkali metals or alkali metal naphthalenides such as sodium naphthal-enide Na+N", as a mechanistic probe over the years95 . A 1984 publication96 discloses the possibility of differentiating between the radical 134 and anion 138 cyclization. 

In radical cyclizations of 134 the ratio of the finally formed cis- and trans-cyclopentanes cis- and trans-141 is normally 3.8 91). If l-methyl-5-hexenyl halides 136 PC = Cl, Br) are reacted with Na+ N" in dimethoxyethane (DME) or THF at room temperature the ratio varies between 0.62 and 2.8 for sodium mirror reactions the cis/trans ratio of 141 can be as low as 0.32 96). This suggests that under the reaction conditions, 1-methyl-5-hexenylsodium also cyclizes, with a trans preference, giving [(2-methylcyclopentyl)methyl]sodium trans-139, M+ = Na+. Most of the other anion cyclizations show a similar strong trans preference 94). 

Kven qualitatively, the results for reaelions in Till-, especially, are striking. In this system, the rale constant for the cycli/ation of R- is a thousand limes that for 5-hexenyl halides, where 3-1 O cycli/ation occurs. Despite this, from 2-(3-bu-icnyl)pheml bromide and iodide in Till-, >989 yields of RMgX are obtained, w ith <1.39 QMgX 1112], This seems inconsistent with a dominant pathway R of any kind. 

In fact, such calculations fail for phenyl and 2-(3-butenyl)phenyl halides [112. Cyclopropyl and 5-hexenyl halides are not good models for the corresponding aryl halides. Grignard reactions of the aryl halides give far fewer by-products than predicted from their aliphatic tnodels in D-model calculations (equation 2.6.7) using Tk = 3 x 10 s, a value that describes reactions in DEE and THF of cyclopropyl and 5-hexenyl bromides (Sections 7.2.8-7.2.9). 

In 1979, the reaction of styrenyl and hexenyl halides with an alkali metal thiophenolate and ethanethiolate was reported (Equation (40))130 Reaction yields exceeded 90%, and the products retained the geometry of the starting olefin. In contrast to the stereospecificity of palladium-catalyzed couplings involving vinyl halides, nickel-catalyzed couplings of vinyl halides with thiolates gave mixtures of stereoisomeric products 131... 

One of the fundamental questions about the mechanism is whether the radical is really free in the sense of diffusing from the metal surface.7 For alkyl halides, there is considerable evidence that the radicals behave similarly to alkyl free radicals.8 One test for the involvement of radical intermediates is to determine whether cyclization occurs in the 6-hexenyl system, where radical cyclization is rapid (see Part A, Section 12.2.2). 

Many examples exist for Pd-catalyzed cross-couplings of alkenylzirconocenes with simple carbocyclic aryl or alkenyl halides, whereas few precedents are seen for the coupling of alkenylzirconocenes with heteroaryl halides. Undheim and coworkers reported a Pd-catalyzed cross-coupling of 2,4-dichloropyrimidine with alkenylzirconocene [50]. Hydrozirconation of hexyne readily took place at room temperature with zirconocene chloride hydride in benzene. The resulting hexenylzirconocene chloride (76) was then coupled with 2,4-dichloropyrimidine at the more electrophilic 4 position, giving rise to 2-chloro-4-[( )-l-hexenyl]pyrimidine (77). 

The first palladium alkenyls, pzTpPd C,N-C(Cl) CHCMe2NMe2 (484)144 and the 3-oxo-hexenyl complex 493,160 were obtained systematically by halide displacement and dimer cleavage (Scheme 36). In common with alkyl and aryl systems (462—479, Section III.C.3), the pzTp ligand was in each case concluded to adopt a -coordination mode in solution, on the basis of (i) spectroscopic data, (ii) literature precedent, and (iii) the assumption that the Pd(II) centers in these complexes were too electron rich to permit coordination of the third pyrazole no solid-state data were reported. Both materials are fluxional in solution, and for 484 the slow-exchange limit was attained at —30 °C, with equilibration of the pyrazolyl environments becoming rapid at 79 °C, though the fast exchange limit... 

Not only radical scavengers, radical reduction and/or radical dimerization products but also radical probes were used in order to prove the presence of radicals as intermediates along the S l propagation cycle. Thus the formation of cyclized and uncyclized substitution products was taken as an indication of radical intermediates in the reaction of neopentyl-type halides containing a cyclizable probe of the 5-hexenyl type 2. These reactions were performed with PhS and Ph2P ions as nucleophiles (equation 13)52. 

The first experimental hint for a finite lifetime of an alkyl halide anion radical in homogeneous etheral solution was provided by Garst and coworkers in 1977. From the reduction of 5-hexenyl chloride, bromide and iodide with disodium tetraphenylethylene in 2-methyltetrahydrofuran (MTHF) at 20°C they concluded that radical anions R-X Na were involved and that the order of their stability was R-I Na" >R-Br Na > R-CrNa. ... 

Symons critically discussed the results of Garst and coworkers. He points out that although it is very unlikely that an ion paired halide radical anion R-X exists in the case of R = 5-hexenyl, R X complexes possessing weak residual charge-transfer interactions would also be expected to differ kinetically from each other as the halide is varied. Of special significance for the interpretation of the results obtained with the cyclopropyl halides 50-52 and 118-Hal are the following conclusions of Symons ... 

It is interesting to note that Ashby s investigations of the reactions of alkyl halides with (trimethyltin)sodium and dialkylcuprates by means of the l-methyl-5-hexenyl probe which led to the conclusion that only radicals cyclize 98), have been questioned by Lee and San Fillipo in 1983 " . These authors correctly state that the cyclization alone does not prove a radical pathway. The cis/trans ratios from reactions of the halides 136 with (trimethyltin)sodium (revised 4.8 at 0 °C)96 , however, are consistent with 100% radical cyclization. 

Attempts to prepare methyl- and phenyl-substituted trishomocyclopropenium cations by the ionization of various czx-bicyclop.l.OJhexyl alcohols and halides have been unsuccessful and have led instead to rearranged cyclo-hexenyl (200) and cyclopentenyl (201) cations [Eqs. (5.30) and (5.31)]. Jorgensen s theoretical calculations on the CyHif potential energy surface have shown that the delocalized methyltrishomocyclopropenium cation is less stable than the corresponding classical tertiary ions. 

Indeed. X appears to dominate. Suppose that X/ were 3 x 10 x (value for 3-hexenyl bromide in DEE) for the pathway R (D-model) coniri-bution in reaelions of aryl halides and dial the only produel of pathway X were RMgX. Then the implied extent of pathway X for the reactions of 2-(3-bulenyl)phenyl halides would he >97 i 11 12. ... 

Note All values, except for the L/C ratios, are the yields of products given in millimoles. In runs 1-4, 2.50 mmol of Th +Cl()4 reacted with 1.00 mmol of (5-hexenyl)2Hg in run 5, 0.5 mL of 12 N HC1 reacted with 1.0 mmol of (5-hexenyl)2Hg. The mixture of isomers of (5-hexenyl)2Hg is described in the Experimental Details. After reaction with the mercurial compound was finished in runs 1-4, the products were treated with LiCl (see Experimental Details). This reaction converted ions such as ThR+ into Th and RC1, and RHg+ into RHgCl. This situation accounts for such halides being listed in column 1. aSum of isomeric compounds having M+ (GC-MS) of 298. feSum of isomeric compounds having M + (GC-MS) of 380. 

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