2-Methoxy-l,3-dithiolane

In a new reaction of the Friedel-Crafts type, using 2-methoxy-l,3-dithiolane and a weak Lewis acid such as TiCl4 the ester 45 could be obtained (45). This compound was either hydrolyzed to the 2-formyl derivative or desulfurized with Raney nickel to the 2-methyl compound. 

The preparation of 2-methoxy-l,3-dithiolane (292) is based on the reaction of dichloromethyl methyl ether with the disodium salt of ethanedithiol in acetonitrile (72HCA75). 

Reaction of 1,2-ethanedithiol with dichloromethyl methylether in the presence of sodium results in the formation of the 2-methoxy-l,3-dithiolane (360) (Scheme 65) <72HCA75>, whereas its reaction with phosgene yielded the l,3-dithiolan-2-one (361) <41RTC453>. 

Bis-[ethylthio -methoxy-methan Bis-[ethylthio]-ethoxy-methan Methoxy-methylthio-phenylthio-methan 2-Methoxy-l, 3-dithiolan 2-Methoxy-1,3-dithian 2-Isopropyloxy-l, 3-dithian... 

Position 2 of the ergoline skeleton is highly suitable for synthetic modification of EA by both electrophilic and radical substitution. Many modifications have been reviewed by Rutschmann and Stadler (1978) chlorination, bromination and iodination, nitration and reduction of nitro derivatives to amino derivatives and reaction with 2-methoxy-l, 3-dithiolane affording an intermediate which can be desulfurised to a 2-methyl derivative. Troxler and Hofmann (1959) described the oxidation of lysergic acid diethylamide (LSD) to 2-oxo-3-hydroxy-2, 3-dihydrolysergic acid diethylamide. 

The pivotal step in this sequence is an electrophilic substitution on indole. Although the use of l,3-dithian-2-yl carbanions is well documented, it has been shown only recently that 1,3-dithian-2-yl carbenium ions can be used in a Priedel-Crafts type reaction. This was accomplished initially using 2-methoxy-l,3-dithiane [1,3-Dithiane, 2-methoxy-] or 2-metlioxy-l,3-dithiolane [1,3-Dithiolane, 2-methoxy-] and titanium tetrachloride [Titanate(l —), tetrachloro-] as the Lewis acid catalyst.9 2-Substituted lysergic acid derivatives and 3-substituted indoles have been prepared under these conditions, but the method is limited in scope by the difficulties of preparing substituted 2-methoxy-1,3-dithianes. l,3-Dithian-2-yl carbenium ions have also been prepared by protonation of ketene dithioacetals with trifluoroacetic acid,10 but this reaction cannot be used to introduce 1,3-dithiane moieties into indole. 

Ethano-bridged phthalate ester 56 was obtained by the DA reaction in good yield and was converted to the BCOD-fiised triester 57a, the t-butyl ester group of which was removed by treatment with TFA (Scheme 15.10) [63]. The DA reaction of tosylacetylene (5a) and 2-methoxy-l,3-cyclohexadiene proceeded smoothly to afford a diastereomeric mixture (5 1) of bicyclo[2.2.2]octenone 58 in 73% yield after hydrolysis by silica gel [64]. Diastereomeric 58 was quantitatively converted to dithiolane, which was subject to the ring expansion reaction with tellurium tetrachloride [65]. Dihydro-1,4-dithiin 59 was obtained in 74% yield. The Barton-Zard reaction of 59 with ethyl isocyanoacetate afforded pyrrole-carboxylate 60a (77% yield), which was transformed to both a-hydroxymethylpyrrole 60b and a-firee pyrrole 60c in good yields. 

An excellent method for the preparation of gem-difluoro compounds from aldehydes and ketones consists of conversion of the carbonyl compound to the corresponding 1,3-dithiolane followed by treatment with two equivalents of l,3-dibromo-5,5-dimethylhydantoin (DBH) and pyridinium poly(hydrogen fluoride) (HF-pyridine) in methylene chloride. Attempted extension of this procedure to 7-methoxy-2,2-dimethyl-4-chromanone, however, gave only the dihydro- 1,4-dithiin derivative 1 in 78% yield. This transformation, which proceeded in excellent yield with a variety of 4-chromanones, was found to require only the DBH (i.e. fluoride ion played no role). 

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