Dimethyl(methylthio)sulfonium Tetrafluoroborate Research Articles

Alkyldisulfanium Salts: Isolable, Electrophilic Sulfur Reagents Competent for Polyene Cyclizations.

Tools that can effect electrophilic sulfur-promoted cation-π cyclizations are generally lacking, especially using alkylsulfide-based reagents. Herein we report that combining three different 1,2-dithioethers with Cl2 and SbCl5 generates isolable alkyldisulfanium salts that can effect such reactions. These new reagents can install -SMe, -SEt, and -SCH2CH2CF3 in modest, moderate, or good yield on diverse frameworks, including polyenes that terminate with electron-deficient groups. We also show that reagents such as dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) can accomplish similar chemistry.

ChemInform Abstract: Studies Dealing with Thionium Ion Promoted Mannich Cyclization Reactions.

Treatment of several amido-substituted thioacetals with dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) produces synthetically useful thionium ions that are intercepted by the adjacent nitrogen atom to afford both five- and six-membered alkylthio-substituted lactams as transient intermediates. Further reaction of the alkylthio-substituted lactam with DMTSF generates an N-acyliminium ion, which undergoes cyclization with the tethered aromatic ring to produce an azapolycyclic ring system. Related cyclization sequences occur when amido thioacetals possessing simple olefinic tethers were used. The overall procedure represents an efficient one-pot approach toward various nitrogen-containing ring systems. The cyclization reaction was employed for a synthesis of the core skeleton of the erythrina alkaloid family.

Studies on the Synthesis of (±)-Stenine: A Combined Intramolecular [4 + 2]-Cycloaddition/Rearrangement Cascade

Several cyclic 2-(methylthio)-5-amidofurans containing tethered unsaturation were prepared via the reaction of dimethyl(methylthio)sulfonium tetrafluoroborate (DMSTF) with beta-alkoxy-gamma-dithiane lactams. Thermolysis of these furans resulted in an intramolecular Diels-Alder reaction (IMDAF). The resulting oxa-bridge cycloadducts underwent a subsequent 1,2-methylthio shift to form tricyclic lactams in high yield. Furan 9, annealed to an azepine ring, underwent the IMDAF reaction at or below room temperature. Conformational effects imposed by the placement of a carbonyl group within the tether, combined with a rotational bias about the C(2)-N bond, enhances the rate of the IMDAF reaction of the seven-ring system so that it occurs readily at 25 degrees C. The feasibility of using the cascade sequence in the context of a total synthesis of the Stemona alkaloid (+/-)-stenine was explored. The eventual synthesis of (+/-)-stenine was carried out by an intramolecular Diels-Alder reaction of a 2-amido-5-methylthio-substituted furan containing a trans-pent-3-enoic acid methyl ester side chain in order to create the desired azepinoindole skeleton. This was followed by a series of reductions to set the syn-anti stereochemical relationship at the incipient ring fusion sites present in stenine. All six stereocenters at the azepinoindole core were derived in high stereoselectivity from the functionality present in the rearranged cycloadduct 10. Compound 10 was converted to stenine in 11 additional steps via a sequence that features a Crabtree's-catalyst directed hydrogenation, iodolactonization, and a Keck allylation.

Tandem Pummerer/Mannich Cyclization Cascade of α‐Sulfinylamides as a Method to Prepare Aza‐Heterocycles.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of Azapolycyclic Systems via the Intramolecular [4 + 2] Cycloaddition Chemistry of 2‐(Alkylthio)‐5‐amidofurans.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A New Method for the Preparation of 2‐Thio Substituted Furans by Methylsulfanylation of γ‐Dithiane Carbonyl Compounds.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Tandem Pummerer/Mannich cyclization cascade of alpha-sulfinylamides as a method to prepare aza-heterocycles.

A series of alpha-sulfinylenamides was conveniently prepared by the condensation of a primary amine with a ketone, followed by reaction of the resulting imine with ethylsulfenylacetyl chloride and subsequent oxidation with sodium periodate. When treated with p-TsOH, cyclization occurred to produce fused isoquinoline lactams by a mechanism that involves an initial Pummerer reaction followed by a subsequent cyclization of the resulting N-acyliminium ion onto the tethered aromatic ring. The isolation of a single diastereomer was rationalized in terms of a Nazarov-type 4pi-electrocyclic reaction followed by pi-cyclization onto the least hindered side of the N-acyliminium ion. Another method that was used to generate the alpha-acylthionium ion intermediate involved the reaction of bis(ethylsulfenylacetyl)acetamides with dimethyl(methyl)thiosulfonium tetrafluoroborate (DMTSF). Treatment of several bis-ethylsulfenylenamides with DMTSF delivered novel spiro-heterocycles as single diastereomers in good yield by a related process. The convergency and stereochemical control associated with this cascade sequence make it particularly suited for the assembly of natural product scaffolds. Some preliminary studies were directed toward both mesembrine and deethylibophyllidine. When the model Z-enamido sulfoxide 33 was heated with p-TsOH, a 80% yield of tosylate 34 was obtained as a single diastereomer. In this case, the carbocation intermediate derived from cyclization onto the terminal pi-bond was trapped with p-TsOH from the least hindered face, opposite the angular carbomethoxy and methyl groups. Related cyclization cascades were also found to occur with systems containing tethered indole rings.

Synthesis of azapolycyclic systems via the intramolecular [4 + 2] cycloaddition chemistry of 2-(alkylthio)-5-amidofurans.

A series of 2-(methylthio)-5-amidofurans containing tethered unsaturation were prepared via the reaction of dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) with beta-alkoxy-gamma-dithiane amides 13-16 and 27-32 in 40-70% yield. Thermolysis of these furans resulted in an intramolecular Diels-Alder reaction (IMDAF). With the exception of 45 and 46, the oxa-bridged cycloadducts could not be isolated but immediately underwent a 1,2-methylthio shift to form bicyclic lactams in 60-100% yield. It was determined that incorporation of the amido carbonyl in the tether allowed the IMDAF reaction to proceed at a lower temperature. A dramatic example of this is seen in the IMDAF reaction of furan 35, in which the presence of an amido carbonyl as part of the dienophile tether, as opposed to the annealed ring (66) or the lack of a carbonyl (67), was necessary for the cycloaddition to occur. Furan 37, annealed to an azepine ring, underwent the IMDAF reaction at or below room temperature. To identify structural features that promote the IMDAF reaction, a computational study was undertaken. Ground-state and transition-state energies were calculated for furans 17, 33, 37, and 64 using the Becke 3LYP/6-31G model. The theoretical results were in good agreement with those observed. The results indicate that the incorporation of an amide carbonyl as part of the tether system works to place the dienophile in closer proximity to the furan ring, thereby lowering the activation energy needed to reach the transition state.

A new method for the preparation of 2-thio substituted furans by methylsulfanylation of gamma-dithiane carbonyl compounds.

Several related methods for the preparation of differentially substituted 2-thiofurans are described. The general procedure involves the formation of a thionium ion from a gamma-dithianyl substituted carbonyl compound followed by cyclization of this reactive intermediate onto the tethered carbonyl group. Two methods for thionium ion generation were explored. One of these involved an acid-catalyzed reaction of beta-ketenedithioacetals, prepared from the condensation of 2,2-bis(methylsulfanyl)acetaldehyde with a variety of ketones. Cyclization followed by loss of methane thiol gave 2-thiofurans 17, 18 and 23, 24 in 70-90% yield. Attempts to prepare 5-heteroatom substituted 2-thiofurans from the corresponding beta-ketenedithioacetal amides or esters were unsuccessful, leading to 1,2-thio rearranged products. A more successful route involved the reaction of beta-acetoxy-gamma-thianyl carbonyl compounds with dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF). Treatment of the dithiane with this reagent resulted in the smooth generation of a thionium ion. Cyclization followed by loss of acetic acid afforded thiofurans 17, 18, 23, 47-49, 51, and 61-64 in 40-100% yield. The N-butenyl substituted thioamido furan furnished a rearranged hexahydropyrroloquinolin-2-one in high yield when heated at 110 degrees C.

A New Construct of the cis-3a-Aryloctahydroindole Skeleton via the [4+2] Cycloaddition of Furanyl Carbamates

Several 2-methylthio-5-amidofurans containing tethered unsaturation were prepared via the reaction of dimethyl(methylthio)-sulfonium tetrafluoroborate (DMTSF) with β-alkoxy-γ-dithiane amides. Thermolysis of these furans resulted in an intramolecular Diels-Alder reaction (IMDAF). The resulting oxa-bridged cycloadducts underwent a subsequent rearrangement to form bicyclic lactams. Model studies were directed toward mesembrine as well as the core skeleton of the 3,4-benzoerythrinane skeleton. Using this cascade sequence, a formal synthesis of the alkaloid erysotrine was accomplished.

Cyclization–cycloaddition cascades for the construction of azapolycyclic ring systems

Cyclic 2-amidofuranones were obtained from the Rh(II)-catalyzed reaction of alpha-diazoketo substituted pyrrolidine derivatives. These compounds are derived by a [1,4]-hydrogen transfer from an initially formed carbonyl ylide dipole. Acylation of the amido-substituted furanone with pivalyl chloride provided a fused amidofuran, which underwent bimolecular Diels-Alder cycloaddition with N-phenylmaleimide. The Rh(II)-catalyzed decomposition of ethyl 2-diazo-3-oxo-(2-oxo-1-pent-4-enoyl-pyrrolidine-3-yl)propionate was also examined. In this case, the alkenyl group tethered to the amido carbonyl underwent smooth intramolecular [4+2]-cycloaddition with the amidofuran obtained from the acylation reaction. An alternate route for the synthesis of cyclic amidofurans was developed using a Pummerer induced cyclization of the thiophenyl substituted acetal derived from the aldol reaction of methoxyphenylsulfanyl acetaldehyde with α-valerolactam. Treatment of the amido-substituted acetal with dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) generated an oxonium ion, which readily cyclized onto the adjacent carbonyl group. The amidofuran that was formed underwent an intramolecular Diels-Alder reaction when heated at 110°C in toluene. Subsequent ring opening of the transient [4+2]-cycloadduct followed by elimination of methanol and tautomerization of the resulting cyclohexadienone gave rise to the observed phenolic lactam in good overall yield.Key words: intramolecular, cyclization, Diels-Alder, diazo-ketoamide, rhodium(II).

Intramolecular [4+2]-cycloaddition reactions of cyclic 2-thiomethyl-5-amidofurans

Cyclic 2-thiomethyl-5-amidofurans possessing tethered π-bonds were prepared by a dimethyl(methyl-thio) sulfonium tetrafluoroborate (DMTSF) induced cyclization of various amido dithioacetals. Upon heating, these systems undergo an intramolecular 4+2-cycloaddition reaction. The initially formed Diels–Alder cycloadduct further rearranges by ring opening of the oxygen bridge followed by a subsequent 1,2-thiomethyl shift.

ChemInform Abstract: Stereoselective Synthetic Approaches to Highly Substituted Cyclopentanes via Electrophilic Additions to Mono-, Di-, and Trisubstituted Cyclopentenes.

Electrophilic additions to allylically substituted alkenes are of broad synthetic utility. The control of stereoselectivity in such reactions has attracted considerable interest. However, the effect of allylic and homoallylic substituents in cyclopentenyl systems has not been investigated systematically. Studies on a series of mono, di-, and trisubstituted cyclopentenes are reported in which trans-vicinal-additions favor a syn-selective approach of electrophiles to the cyclopentene system. The formal addition of HOBr, HOCl, CH3SCl, and dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF)/NaN3 with a variety of cyclopentene substrates has been carried out, and the effects of various allylic substituents on these selectivities have been examined. Additions of HOBr, HOCl, and DMTSF to highly functionalized substrates proceed predictably with syn selectivity, giving predominantly or exclusively one product. Methanesulfenyl chloride additions are less predictable, but can be tuned by suitable alteration of ...

Stereoselective synthetic approaches to highly substituted cyclopentanes via electrophilic additions to mono-, di-, and trisubstituted cyclopentenes.

Electrophilic additions to allylically substituted alkenes are of broad synthetic utility. The control of stereoselectivity in such reactions has attracted considerable interest. However, the effect of allylic and homoallylic substituents in cyclopentenyl systems has not been investigated systematically. Studies on a series of mono, di-, and trisubstituted cyclopentenes are reported in which trans-vicinal-additions favor a syn-selective approach of electrophiles to the cyclopentene system. The formal addition of HOBr, HOCl, CH(3)SCl, and dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF)/NaN(3) with a variety of cyclopentene substrates has been carried out, and the effects of various allylic substituents on these selectivities have been examined. Additions of HOBr, HOCl, and DMTSF to highly functionalized substrates proceed predictably with syn selectivity, giving predominantly or exclusively one product. Methanesulfenyl chloride additions are less predictable, but can be tuned by suitable alteration of solvent and substrate. Results have proven useful in total syntheses of (+)-trehazolin and (+)-allosamidin.

Studies dealing with thionium ion promoted mannich cyclization reactions.

Treatment of several amido-substituted thioacetals with dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) produces synthetically useful thionium ions that are intercepted by the adjacent nitrogen atom to afford both five- and six-membered alkylthio-substituted lactams as transient intermediates. Further reaction of the alkylthio-substituted lactam with DMTSF generates an N-acyliminium ion, which undergoes cyclization with the tethered aromatic ring to produce an azapolycyclic ring system. Related cyclization sequences occur when amido thioacetals possessing simple olefinic tethers were used. The overall procedure represents an efficient one-pot approach toward various nitrogen-containing ring systems. The cyclization reaction was employed for a synthesis of the core skeleton of the erythrina alkaloid family.

Oligomeric flavanoids. Part 27. Interflavanyl bond formation in procyanidins under neutral conditions

Dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) and silver tetrafluoroborate (AgBF 4) activate the C 4S bond in the 4-thioethers of flavan-3-ols toward carbon nucleophiles to permit formation of the interflavanyl bond in procyanidins under neutral conditions.

Synthesis of monofluorinated compounds from methallyl chloride

Monofluorinated organic compounds gain an important position as biologically active substances or intermediates for synthesis of such compounds. However, the selective introduction of one fluorine substituent is sometimes difficult. Triethylamine tris-hydrofluoride (Et 3N,3HF) in combination with different electrophiles are effective systems for monofluorination of olefins [1–3]. The halofluorination [1] of methallylchloride ( 1) gives mainly the corresponding Markovnikov addition products 2 and some traces of anti-Markovnikov orientated compounds 3, while the bromofluorination of allyl chloride gave both regioisomers in a 4:1 ratio [4]. When using the combination dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF)/ Et 3N,3HF [2] a mixture of mainly 2 (XSMe), some 3 (XSMe) and some amount of 4 (RMe) has been isolated. ▪ The fluorosulfenylation, however, was not realized using phenylsulfenyl chloride in combination with Et 3N,3HF; 1,3-dichloro-2-methyl-2-phenylthio-propane ( 5) was formed which is rearranged to 4 (RPh) using Olah's reagent (−78°C to 0°C) or Et 3N,3HF (16h, 60°C). Treatment of 5 with AgF in dichloro-methane at −30°C gave the desired fluorinated compound 2 (XSPh).

Alkylthio-substituted (aza)fulvalenes

Bis-methylthio-5-aza-1,4-dithiafulvalenes ( 5 - 7 ) and bis-methylthio-2-azacalicenes ( 9 , 10 ), resp., are formed when pyrroles and indole are reacted with tris-methylthio-1,3-dithiolium tetrafluoroborate and tris-methylthio-cyclopropenylium tetrafluoroborate, resp., the latter readily prepared from tetrachlorocyclopropene and dimethylmethylthiosulfonium tetrafluoroborate. Poly-alkylthio-dithiafulvalenes ( 12 , 13 ) and their 5,8-diaza derivatives can be generated through the condensation of pentakis-methylthio-cyclopentadiene and tris-ethylthio-imidazole, resp., with dithiolium salts.