2-Lithio-l ,3-dithiane

The possibility of activating the indole nucleus to nucleophilic substitution has been realized by formation of chromium tricarbonyl complexes. For example, the complex from TV-methylindole (215) undergoes nucleophilic substitution with 2-lithio-l,3-dithiane to give a product (216) which can be transformed into l-methylindole-7-carbaldehyde (217) (78CC1076). 

The use of ethyl ethylthiomethyl sulphoxide in this reaction leads to the desired addition products in much better yields (95-97%). These products were then converted into ketene dithioacetal monoxide derivatives 430 by a sequence of reactions (equation 258)505. Reaction of 2-lithio-l,3-dithiane-l-oxide with benzophenone affords a mixture of the diastereoisomeric tertiary alcohols 431 in a ratio which is temperature dependent (cis trans changes from 3 1 at — 78 °C to 1 1 at room temperature)268. 

Halogenation of 106 with triphenylphosphine, iodine, and imidazole provided the iodo derivative 109. On treatment with lithium aluminum hydride, 109 was converted into two endocyclic alkenes, 110 and di-O-isopro-pylidenecyclohexanetetrol, in the ratio of 2 1. Oxidation of 110 with dimethyl sulfoxide - oxalyl chloride afforded the enone 111.1,4-Addition of ethyl 2-lithio-l,3-dithiane-2-carboxylate provided compound 112. Reduction of 112 with lithium aluminum hydride, and shortening of the side-chain, gave compound 113, which was converted into 114 by deprotection. ... 

The following is an example for a sequential one-pot epoxide formation/nucleophilic opening process using (S)-4-(benzyloxy)-l,2-butanediol, iV-(p-tohienesulfonyl)-imida-zole, and 2-lithio-l,3-dithiane ... 

Carbolithium compounds of moderate reactivity open the O—C bond of cyclic sulfate esters or cyclic sulfamidates to produce new C—C links, as shown, for example, in equation 112 for a chiral cyclic sulfamidinate and 2-lithio-l,3-dithiane (380a). More reactive organolithium species, such as n-BuLi and PhLi, yield mixtures of products, probably due to attack on the S atom of the sulfonamido group too °. 

As expected, 2-halo-l,3-dithianes react with nucleophiles under Sn conditions. Suitable nucleophiles are enamines <2002TL9517, 2004T6931> and phenols <1997MOL7>. The reaction with EtOC(S)S K, followed by oxidation, provided a xanthate which generated a 1,3-dithiane 1-oxide radical upon treatment with Bu3SnH (Scheme 69) <2004T7781>. An efficient one-carbon radical precursor has also been obtained by addition of 2,2,6,6-tetramethyl-piperidine-l-oxyl (TEMPO) to 2-lithio-l,3-dithiane. The reactivity of this compound has been demonstrated <2005S1389>. 

The reaction of 2-lithio-l,3-dithiane with chlorodiphenylphosphine under oxidative conditions furnished an open-chain reaction product with a formyl thioester and a thiophosphinate moiety (Equation 54) <2003TL5293>. 

Examples of sugar homologation based on the use of 2-lithio-l,3-dithiane (2-LDT, 13) are surprisingly rare relative to the popularity of this reagent [25]. Stereoselective chain extension of a partially protected hexose, 2,3 5,6-di-0-isopropylidene-ot-D-mannofuranose (14), into a D-glycem-D-galacto-heptose derivative (16) was reported by Paulsen and his coworkers several years ago [26] (Scheme 5). 

H. Chikashita, T. Nikaya, and K. Itoh,.Iterative and stereoselective one-carbon homologation of 1,2-O-cyclohexylidene-D-glyceraldehyde to aldose derivatives by employing 2-lithio-l,3-dithiane as a formyl anion equivalent, Nat. Product Lett. 2 183 (1993). 

The dithiane derivative 60 (Scheme 14) is such a compound, it being made from 2,3 5,6-di-0-isopropylidene-D-mannose by treatment with 2-lithio-l,3-dithiane to give a heptose dithioacetal that was refunctionalized at C-2-C-3 by way of the C-l anion and then converted to the 6,7-epoxide following selective acid-catalyzed cleavage of the 6,7-acetal ring. Treated with n-butyllithium it gives, in 70% yield, the cyclized 61, which is efficiently convertible into validatol 62, a component of validamycin A, by desulfurization with Raney nickel and de-O-protection by use of boron tribromide in dichloromethane [31]. 

The dibromobutene 149 could be monosubstituted using 2-lithio-l,3-dithiane as a carboxylic acid precursor, followed by substitution of the remaining bromide with sodium azide as the amine precursor (Scheme 32). The azide was reduce under Staudinger conditions and acy-lated. After separation of the EIZ isomers, further functional group transformations gave the dimethyl-substituted Gly-Gly alkene isostere 152J123 ... 

It should be noted with (3), (4), (13) and (14) only hard lithium nucleophiles are tolerated, while for (5), (6), (7) and (15) the range of useful lithium nucleophiles, e.g. including lithio-l,3-dithianes and lithium enolates, is broader. In addition, none of these Michael acceptors react with organocuprates, Grig-nard reagents or stabilized carbanions. 

More reactive anions such as the 2-lithio-l,3-dithiane derivatives, phenyllithium and r-butyllithium do not require a special solvent and proceed in high yield in THF. While HMPA is known to suppress the migratory insertion to CO in anionic complexes,127 it does not deter the CO insertion in these cases no example of direct alkylation is reported. The only electrophile which adds without CO insertion is the proton, as discussed above. Good alkylating agents (primary iodides and triflates, ally bromide, benzyl... 

Review. A recent review of 1,3-dithianes and 2-lithio-l,3-dithianes covers the literature of 1977-1988 (126 references). 

Let us turn now to the other coupling partner, aldehyde 58 it was synthesised by the pathway shown in Scheme 17.18. The first step was a Sharpless catalytic asymmetric epoxidation on ( )-crotyl alcohol with the oxidant derived from (—)-diethyl tartrate. An in situ derivatisation with r-butyldiphenylsilylchloride was then performed. The desired epoxide 59 was readily isolated in 76% overall yield after chromatography. Treatment of 59 with 2-lithio-l,3-dithiane in THF and 1,3-dimethyl-3,4,5,6-tetrahydro-2(l/7)-pyrimidinone (DMPU also known as N,N-... 

A new synthesis of the pyran (251), confusingly named linaloyl oxide, has been reported. 2,6-Dimethyl-l,2-epoxyhept-5-ene gave (252) with 2-lithio-l,3-dithian almost quantitatively, and boron trifluoride-catalysed cyclization to (253) readily led to (251).353... 

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