Three-component dithiane

A Hg(II)-catalysed rearrangement of P-hydroxy Mv-dithiane 147 gave 1,4-dithiepines 148 <070L4061>, while the 1,4-dithiepines 149 were synthesised as scaffolds for medicinal chemistry in good yield by the three component coupling of ethanedithiol, malononitrile and an aromatic aldehyde <07JOC3443>. 

The viabihty of this new Type II ARC involving threefold domino reactions was demonstrated by developing a one-flask three component coupling protocol using 1,3-dithiane epoxy compound 176 as linchpin (Scheme 4.33) [59]. Thus,... 

ARC process [67]. The initiating nucleophiles included either lithiated 2-methyl-1,3-dithiane or lithium di-n-butylcuprate, which on reaction with these linchpins (191-193), followed by trapping of the rearranged anion 172 by allyl bromide as electrophile, provide three-component adducts such as 194-196 in 58-68% overall yields (Scheme 4.38) [63, 67]. Of particular note is the stereochemical outcome of these reactions. High diastereoselectivity was observed with linchpins possessing a methyl substituent a to the silyl group, when a phenyl moiety serve as ASG (Scheme 4.38, Eq. (2)), while poor diastereoselectivity is observed when a phenylthio moiety is employed as the ASG irrespective of the presence of a-substituent (Scheme 4.38, Eq. (3)) [67, 68]. 

Micalizio and coworker reported a three-component coupling sequence for the synthesis of substituted pyridines in 2012 [121]. The reaction proceeded through nucleophilic addition of a dithiane anion to an Q ,/3-unsaturated carbonyl followed by metallacycle-mediated union of the resulting allylic alcohol with preformed trimethylsilane-imines (generated in situ by the low temperature reaction of lithium hexamethyldi-silazide with an aldehyde) and Ag(I)- or Hg(II)-mediated ring closure. Good yields of substituted pyridines were isolated. 

The three-component process with 2-t-butyldimethylsilyl-l,3-dithiane has been further optimized to incorporate two different epoxides, employing solvent as a means to control the 1,4-Brook rearrangement (eq 9). In this protocol, lithiation and alkylation of the first epoxide are conducted in Et20 rather than THF to prevent premature silyl migration. Introduction of HMPA (or DMPU) with the second epoxide in Et20 initiates the Brook process subsequently leading to the desired unsymmetrical, three-component adducts. 

Chemists10 at the Stanford Research Institute used Corey s procedure for the synthesis of (5 below) and (7 below), two of the three principal components of the sex attractant of the bark beetle, Ips confusus. The former was synthesized by reaction of 2-isobutyl-l,3-dithiane (2) with 2-bromomethy[butadiene (1) followed by deblocking with mercuric chloride and cadmium carbonate to give methyl-6-... 

Smith and coworkers next extended Type II ARC domino protocol beyond dithiane arena by designing a variety of effective ARC linchpins with different ASGs capable of three and four component couplings. In their first effort toward this goal, they developed readily available 2-bromoallylsilane [62a], and subsequently, allyltrimethylsilane 185 [63], and recently o-TMS (trimethylsilyl) benzaldehyde 188 as promising linchpins for Type II ARC process [64, 65]. However, domino anionic relay reactions with these linchpins 185 and 188 are not discussed in this chapter, since they are not initiated by nucleophilic substitution as the first step. 

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