Pummerer reactions, acetic anhydride

An alternative approach, which has only been applied to heteroaromatic thiepins, is provided by the Pummerer reaction.70,71 The careful double oxidation of hetarenothicpancs to the corresponding S-oxides, followed by brief treatment with acetic anhydride at 150 °C in the absence of oxygen, gives the heteroaromatic thiepins in moderate yield. 

Due to their thermal instability, this method cannot be applied to the preparation of benzo-thiepins. Although the ft-oxo sulfoxide moiety in precursors such as 5-methoxy-4-phenyl-l-benzothiepin-3(2/7)-one 1-oxide makes them candidates for a Pummerer reaction, treatment with acetic anhydride and triethylamine at - 30 C results in preferential enol acetylation to afford the corresponding 1-benzothiepin 1-oxide.14... 

The tetrahydrotrithiepin 1 is oxidized to an 5-oxide of undetermined structure, which undergoes a Pummerer reaction with acetic anhydride to give 1,2,5-trithiepin (2) in low yield.432... 

Whereas conversion of sulfoxides to the corresponding a-acyloxysulfides by acid anhydrides, for example acetic anhydride, the Pummerer reaction [1], has been known for quite a time, the conversion of sulfoxides with silylating reagents via the unstable intermediate O-silyl compounds to a-silyloxysulfides, the Sila-Pummerer reaction is a relatively new reaction, which has recently been reviewed [1—4-]. 

The Pummerer reaction of conformationally rigid 4-aryl-substituted thiane oxides with acetic anhydride was either stereoselective or stereospecific, and the rearrangement is mainly intermolecular, while the rate-determining step appears to be the E2 1,2-elimination of acetic acid from the acetoxysulfonium intermediates formed in the initial acetylation of the sulfoxide. The thermodynamically controlled product is the axial acetoxy isomer, while the kinetically controlled product is the equatorial isomer that is preferentially formed due to the facile access of the acetate to the equatorial position . The overall mechanism is illustrated in equation 129. 

The differing nucleophilicity of acetate and trifluoroacetate anion determined the manner in which naphtho[l,8-/yt]-l,5-dithiocinc sulfoxide 127 rearranged on treatment with acetic and trifluoroacetic anhydrides. In both cases, the reaction proceeded through formation of a disulfonium dication 128, but the final products were different. When acetic anhydride was used, the reaction afforded the corresponding a-acetylsulfide 130, a normal product of the Pummerer rearrangement, while trifluoroacetic anhydride caused isomerization with formation of dithioacetal 132 (see Scheme 16) <1995HAC559>. 

A stereoselective Pummerer reaction was first observed with the diastereomeric cyclic sulfoxides 269. It was found (299) that when the CIS- or tra 5-sulfoxides 269 are heated for several hours with acetic anhydride, the corresponding cis- or fraws-acetoxysulfides 270 are formed with a stereospecificity exceeding 85%. 

In 1974 the first example of asymmetric induction in an intramolecular Pummerer reaction was observed and reported. Stridsberg and AUenmark (300) treated optically pure o-benzylsulfinylbenzoic acid 271 with acetic anhydride in the presence of dicyclohexyl-carbodiimide (DCC) and found that the Pummerer reaction product, 3,l-benzoxathian-4-one 272, was optically active. The sign and optical rotation values ([alp varied from +42° to -11°) of 272... 

Recently, new examples of asymmetric induction in the Pummerer reaction of chiral sulfoxides have been described. Oae and Numata (301) reported that the optically active a-cyanomethyl p-tolyl sulfoxide 275 undergoes a typical Pummerer rearrangement upon heating with excess of acetic anhydride at 120°C, to give the optically active a-acetoxy sulfide 276. The optical purity at the chiral a-carbon center in 276, determined by means of H- NMR spectroscopy using a chiral shift reagent, was 29.8%. 

Selenides (290) and (292) were oxidized to the unstable selenoxides (298) and (299) by aqueous hydrogen peroxide under controlled conditions or by sodium metaperiodate. When selenoxide (298) was subjected to the Pummerer reaction using acetic anhydride in the presence of N- phenylmaleimide, a mixture of exo/endo adducts (144) was obtained in 58% yield, indicating the transient formation of the selenolo[3,4-c]thiophene (143 Scheme 100) <77H(6)1349). 

The Pummerer reaction of sulfinyl compounds involves the formation of an a-functionalized sulfide [244, 245] from a sulfoxide. Acetic anhydride is commonly used as the electrophile, which adds to the sulfoxide to yield a sulfonium salt, and the rearrangement occurs through successive formations of an ylide (rate-determining step) and an alkylidene sulfonium, trapped by a nucleophile, or stabilized by a proton loss with formation of a vinyl sulfide. 

Vinylic sulfoxides such as 1 react readily with electrophiles to give highly reactive species, and the overall reactions have been likened to "generation" of the synthon 2. Treatment of 1 with TFAA, for example, results in what is referred to as an "additive Pummerer reaction", and gives the diester 3. Reaction of 1 with triflic anhydride and sodium acetate in acetic anhydride, by contrast, gives an 85% yield of the protected aldehyde 4. 

Oxidation of 1,2,5-trithiepine 44 with ///-chloroperoxybenzoic acid in CHCI3 resulted in the formation of crystalline monosulfoxide 130, which underwent Pummerer rearrangement upon reaction with acetic anhydride to furnish 6,7-dihydro[l,2,5]trithiepin 45 (Scheme 31) <1997JOC2432>. 

Pummerer rearrangement of this sulfoxide in acetic anhydride under reflux furnished 3,4-dihydrothiepin 45. The trithiepine 46 was obtained upon oxidation and Pummerer rearrangement of 3,4-dihydrothiepine. Alternatively, 3,4-dihydrothiepine was also obtained by the reaction of 1,2,5-trithiepine with A-chlorosuccinimide, followed by treatment with EtjN <1997JOC2432>. 

First, the normal Pummerer reaction of syn- and anti-sulfoxides with hot acetic anhydride was examined. It was found that both gave the same 80 20 ratio of... 

In comparison to some of the other activation methods however, the dimethyl sulfoxide-acetic anhydride procedure has certain disadvantages. The method often requires the use of long reaction times (1 24 h), which can result in many side reactions, especially with sensitive substrates. Notable in this respect is that it is not uncommon for this procedure to result in the formation of substantial yields of the thiomethyl ethers obtained from the Pummerer rearrangement product as described above. In fact upon attempted oxidation of cholesterol with this system, the major product obtained was the corresponding (methylthio)methyl ether. Acetates may also be formed if the alcohol is unhindered. For example the sugar derivative (9) reacts under these conditions to form an enol acetate (derived from the requir carbonyl compound) in 40% yield contaminated with 30% of the acetate (10 equation S). ... 

The methylthiomethyl ether (MTMOR) Tertiary hydroxyl groups, which are susceptible to acid-catalyzed dehydration, can be easily protected as MTM ethers and recovered in good yield. The MTM ether of a hydroxyl group can be formed either by a typical Williamson ether synthesis or on reaction with dimethylsulfoxide (DMSO) and acetic anhydride (AC2O). In the latter case, the reaction proceeds with the Pummerer rearrangement " (Scheme 1.25). 

The Pummerer reaction of optically active R)- +)-a-(p-tolylsulfinyl)-A/,Al-dimethylacetamide with Acetic Anhydride in the presence of 1,3-Dicyclohexylcarbodiimide is highly stereoselective, affording the corresponding a-acetoxy sulfide in moderate yield but with nearly 70% ee (eq 2). The recovered starting sulfoxide is obtained in 63% yield. 

---