Mechanisms of sulfanyl (RS) migrations: synthesis of heterocycles

Thiiranium (episulfonium) ions had been acknowledged as reaction intermediates for many years, but it was not until 1977 that Nicolaou demonstrated systematically that these reactive heterocyclic cations could be trapped by carboxylic acids to give lactones. In the years that followed this report, extensive research greatly extended the scope of this reaction, particularly with regard to the methods for generating thiiranium ions, the types of nucleophiles that are compatible with this reaction, and the selectivity involved in the cyclization reactions. For many years we have been using thiiranium ions for the synthesis of saturated heterocycles. Whereas Nicolaou's method relied on electrophilic sulfenylation of alkenes, we have generated thiiranium ions by displacement of a leaving group with neighboring-group participation by a sulfanyl group. Many of the examples we have reported are of cyclizations that are reversible and so where two (and in some cases more) products can result, the outcome of the reactions provides fundamental information about the relative stability of different heterocyclic ring systems. This Review will begin with a brief introduction to sulfanyl participation as a method for generating thiiranium (and thiolanium) ions, and will go on to explore the idea of using sulfanyl migrations in synthesis. Initially, emphasis will be placed on mechanisms of [1,2] sulfanyl migrations: we will look specifically at [1,2] sulfanyl migrations (usually PhS) with elimination, substitution, and cyclization. Emphasis will then shift to the factors that affect the outcome of cyclization reactions. In particular, we will cover cyclizations with hydroxy nucleophiles and examine situations in which there are more than one hydroxy nucleophile present. We will also examine cyclizations with other nucleophiles, namely amines and sulfides. After our discussion of [1,2] sulfanyl migrations, we will look very briefly at the scope of [1,4] sulfanyl participation, before finally drawing up some guidelines that (we hope) will help other organic chemists take advantage of the rearrangement reactions that the sulfanyl group has to offer.     

Synthesis of β‐Hydroxy α‐Sulfanyl Esters by Using Nanocrystalline Magnesium Oxide

Aldol‐type reaction between electron deficient aldehydes and sulfonium salts to afford the corresponding β‐hydroxy α‐sulfanyl esters in moderate‐to‐good yields by using nanocrystalline MgO is described. The sulfanyl group is a useful group for further transformations in organic synthesis. Low R_f‐value isomer is anti‐configured as revealed by X‐ray diffraction study and consistent with the assignment of ¹H‐NMR spectrum.     

Sulfanyl radical addition–cyclization and its synthetic application

This review summarizes a new efficient carbon–carbon bond-forming reaction based on sulfanyl radical addition–cyclization, which proceeds by the formation of a carbon-centered radical species generated by the addition of a sulfanyl radical to a multiple bond and then intramolecular addition of the resulting carbon-centered radical to a multiple bond. The synthetic potentiality was demonstrated by the syntheses of anantine, oxo-parabenzlactone, cispentacin, vitamin D, and α-kainic acid.     

Facile synthesis of 3-aryl-1-((4-aryl-1,2,3-selenadiazol-5-yl)sulfanyl)isoquinolines

A new series of 1,2,3-selenadiazoles containing an aryl or a 3-arylisoquinoline sulfanyl moiety at carbons 4 and 5, respectively, was prepared by cyclization of the respective semicarbazones in the presence of selenium(II) oxide and tetrahydrofuran at 70–75°C. Semicarbazones required for the reaction were obtained from 2-((3-arylisoquinolin-1-yl)sulfanyl)-1-phenylethanones, I, by a reaction with semicarbazide hydrochloride in ethanol/water mixture and potassium acetate base.     

Application of directed metalation in synthesis. Part 6: A novel anionic rearrangement under directed metalation conditions leading to heteroannulation

A short and efficient synthesis of condensed 1,4-oxathiin-2-ones from easily available phenols is described. The key step in this synthesis is a hitherto unreported anionic rearrangement under directed metalation conditions. The rearrangement occurs after side chain deprotonation of a methyl sulfanyl group by an O-carbamate directed metalating group and the reaction mixture is kept at room temperature for 8-12 h. Acid-mediated cyclisation of the rearranged product affords [1,4]oxathiin-2-one.     

Synthesis of N-arylsulfonyl-2-aryl(hetaryl)aminoacetic acids

Hydrolytic transformations of 4-[2,2,2-trichloro-1-(arylsulfonylamino)-and-(ethoxycarbonylamino)ethyl]phenyloxy(or sulfanyl)acetic acids under microwave irradiation in alkaline medium involve both trichloromethyl group and ester fragment to give N-arylsulfonyl-2-[4-carboxymethyloxy(or sulfanyl)phenyl]-2-aminoacetic acids in good yields. Hydrolysis of methyl 4-[2,2,2-trichloro-1-(arylsulfonylamino)ethyl]phenyloxy(or sulfanyl)acetates without microwave activation occurs only at the ester group with quantitative formation of 4-[2,2,2-trichloro-1-(arylsulfonylamino)ethyl]phenyloxy(or sulfanyl) acetic acids. N-[2,2,2-Trichloro-1-(1-naphthyl, 2-furyl, and 1-methylindol-3-yl)ethyl]-4-chlorobenzenesulfonamides in alkaline medium under microwave irradiation were converted in 10–15 min into the corresponding N-(4-chlorophenylsulfonyl)-2-aryl-2-aminoacetic acids in preparative yields.     

Synthesis of α‐phosphonylated phosphonium and sulfonium ylides: Study of their thermal behavior

The additions of two equivalents of trialkylphosphites onto phosphonodithioformates produce stabilized α‐sulfanyl‐α‐phosphonyl phosphonium ylides. Their subsequent reaction with alkyl or benzyl halides gives stabilized sulfonium ylides. Thermal treatment of these phosphonium and sulfonium ylides leads to α‐sulfanyl methylene bis‐phosphonates through protonation–dealkylation intramolecular reactions. © 2009 Wiley Periodicals, Inc. Heteroatom Chem 20:164–171, 2009; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20530     

A Reaction of Triazoles with Thioesters to Produce β‐Sulfanyl Enamides by Insertion of an Enamine Moiety into the Sulfur–Carbonyl Bond

N‐Sulfonyl‐1,2,3‐triazoles react with thioesters in the presence of a rhodium(II) catalyst to produce β‐sulfanyl enamides in a stereoselective manner. The reaction proceeds through generation of an α‐imino rhodium carbene complex, nucleophilic addition of the sulfur atom of a thioester onto the carbenoid carbon atom, and subsequent intramolecular migration of the acyl group from the sulfur atom to the imino nitrogen atom. The method is successfully applied to a ring‐expansion reaction of thiolactones, thus leading to the formation of sulfur‐containing lactams.     

Reaction of Potassium 1,1,3,3-Tetracyano-2-(2,2-dimethylpropanoyl)propenide with 2-Sulfanylethanol

The reaction of potassium 2-(2,2-dimethylpropanoyl)-1,1,3,3-tetracyanopropenide with an equimolar amount of 2-sulfanylethanol afforded 2-{5-amino-2-(tert-butyl)-4-cyano-2-[(2-hydroxyethyl)sulfanyl]- 2,3-dihydrofuran-3-ylidene}propanedinitrile, whereas 4-amino-1-(tert-butyl)-1,6-bis[(2-hydroxyethyl)- sulfanyl]-3-imino-1,3-dihydrofuro[3,4-c]pyridine-7-carbonitrile was obtained in the reaction with excess 2-sulfanylethanol.     

Reaction of P(IV) Dithio Acids with <Emphasis Type="Italic">N</Emphasis>-Alkyl-α-chloroketimines

Effect of the substituent on the imine carbon atom on the result of the reaction of P(IV) dithio acids with N-Alkyl-α-chloroketimines has been studied. New types of ketones containing (O,O-diisopropyl phosphorothioyl)sulfanyl and (diphenylphosphinothioyl)sulfanyl groups were synthesized.     

An Efficient Synthesis of Stable Sulfur-Containing Phosphoranes Derived from 1-Methylimidazole-2-thiol

Stable crystalline phosphorus ylides are obtained in excellent yields from the 1:1:1 addition reaction between triphenylphosphine and dialkyl acetylenedicarboxylates in the presence of 1-methylimidazole-2-thiol. These sulfur-containing phosphoranes exist in solution as a mixture of two geometrical isomers as a result of restricted rotation around the carbon-carbon double bond resulting from conjugation of the ylide moiety with the adjacent carbonyl group. Using dibenzoylacetylene as Michael acceptor, yields 2-[1-methyl-1 H -imidazole-2-yl)sulfanyl]-1,4-diphenyl-butane-1,4-dione.     

Aryl ethers of 4-[(2-hydroxyethyl)sulfanyl]pyrimidine derivatives: Pathways of synthesis and fungicidal activity of their salt forms

2-Amino-4-[(2-aryloxyethyl)sulfanyl]-6-methylpyrimidines were obtained by S-alkylation of 2-amino-6-methylpyrimidin-4(3H)-thione with 2-aryloxyethyl chlorides. Since 2-amino-4-[(2-chloroethyl)sulfanyl]-6-methylpyrimidine is prone to in situ intramolecular cyclization it cannot be used in Claisen reaction. The bromination of the target compounds provided 5-bromo derivatives; some of their hydrochlorides exhibited fungicidal activity.     

A tandem multi-component synthesis of 5,7-diaryl-5,6,7,8-tetrahydro-1H-pyrido[3,4-b][1,4]thiazin-2(3H)-ones

The five-component reaction of ethyl 2-[(2-oxopropyl)sulfanyl]acetate, aromatic aldehydes, and ammonium acetate affords two diastereomers of 5,7-diaryl-5,6,7,8-tetrahydro-1H-pyrido[3,4-b][1,4]thiazin-2(3H)-ones via a novel tandem Mannich-enamine-substitution sequence. Presumably, they are generated from ethyl 2-[(4-oxo-2,6-diaryl-3-piperidinyl)sulfanyl]acetates. During the formation of the trans-5,7-diaryl-5,6,7,8-tetrahydro-1H-pyrido[3,4-b][1,4]-thiazin-2(3H)-ones from ethyl 2-[(4-oxo-2,6-diaryl-3-piperidinyl)sulfanyl]acetates, the configuration at the carbon bearing an aryl group adjacent to the enamide CC double bond is inverted via ring opening and closure. When o-substituted benzaldehydes were employed in this reaction, 5,7-diaryl-5,6-dihydro-1H-pyrido[3,4-b][1,4]thiazin-2(3H)-ones were obtained via air oxidation, along with trans-5,7-diaryl-5,6,7,8-tetrahydro-1H-pyrido[3,4-b][1,4]-thiazin-2(3H)-ones.     

Asymmetric induction of the iodolactonization reaction of alpha-sulfurated gamma-unsaturated amides

The 1,3-asymmetric iodolactonization reaction of enantiopure alpha-sulfurated gamma-unsaturated amides has been investigated. With sulfinyl and sulfonyl groups, a poorly stereoselective reaction was observed, whereas with a sulfanyl moiety, the diastereoselectivity can be high as 96:4. The role of the oxygen atom on the sulfur moiety is discussed.     

Efficient Synthesis and Antimicrobial Evaluation of Acyclic Pyrimidine Nucleosides and Their Sulfanyl Analogs

Russian Journal of Organic Chemistry - A facile synthetic approach has been proposed for a new series of uracil acyclic nucleosides and their sulfanyl analogs via reaction of pyrimidine derivatives...     

Condensation of Propan-2-one with Formaldehyde and Propane-2-thiol

Three-component condensation of propan-2-one with formaldehyde and propane-2-thiol in the presence of sodium hydroxide afforded 3-{[(propan-2-yl)sulfanyl)]methyl}but-3-en-2-one or 4-[(propan-2-yl)sulfanyl]-3-{[(propan-2-yl)sulfanyl]methyl}butan-2-one, depending on the amount of the base. The formation of 4-[(propan-2-yl)sulfanyl]-3-{[(propan-2-yl)sulfanyl]methyl}butan-2-one from 4-[(propan-2-yl)sulfanyl]butan-2-one involved aldol condensation of the latter with formaldehyde and subsequent nucleophilic addition of propane-2-thiol to the C=C double bond of intermediate 3-{[(propan-2-yl)sulfanyl]methyl}but-3-en-2-one in the presence of sodium hydroxide.     

Alkylation of 2-Sulfanylbenzoxazole with α-Iodoketones in the Absence of Bases

Reaction of 2-sulfanylbenzoxazole with 1-iodopropan-2-one, 2-iodo-1-phenylethanone, and 2-iodo-1-(thiophen-2-yl)ethanone without solvent and bases afforded bis(benzoxazol-2-yl)disulfonium derivatives in a single preparative stage. The reaction proceeds as a domino-process and includes the alkylation of a sulfanyl group of benzoxazole, the reduction of iodoketone with hydrogen iodide, the oxidation of 2-sulfanylbenzoxazole to disulfide, the alkylation of disulfide atoms of sulfur, and the formation of triiodideanions. The yield of disulfonium derivatives increases twice in the presence of equimolar amount of iodine.     

Radical reaction of chlorophyll derivatives triggered by AIBN

Radical reactions of a C3-vinylated chlorophyll derivative, methyl pyropheophorbide-a, which were induced by thiols and the conventional initiator azobisisobutyronitrile (AIBN) were examined in vitro for the first time. Thiyl radicals attacked regioselectively at the sole C3-vinyl group, and the anti-Markovnikov sulfanyl adducts were obtained as major products. The other peripheral substituents, as well as the chlorin macrocycle, remained intact. The AIBN-induced radical reaction competed with co-oxidation that afforded the C3-formyl chlorin. This method can open new routes to derivatization of vinyl chlorins.     

Regioselective synthesis of 2,8-disubstituted 4-aminopyrido[3,2-d]pyrimidine-6-carboxylic acid methyl ester compounds

We report herein the synthesis of 4-amino-2,8-dichloropyrido[3,2-d]pyrimidine derivatives 2 and their regioselective diversification through S(N)Ar and metal-catalyzed cross-coupling reactions. While amination of 2 took place selectively at C-2, the regioselectivity of thiol or thiolate addition depended on the reaction conditions. Selective C-8 addition was obtained in DMF with Hünig's base and C-2 addition in (i)PrOH. These C-2 or C-8 regioselective thiolations provided an opportunistic way to selectively activate either of the two positions toward the metal-catalyzed cross-coupling reaction. The chloride could be efficiently substituted by Suzuki-Miyaura reaction and the sulfanyl group by Liebeskind-Srogl cross-coupling reaction, demonstrating the orthogonality of both reactive centers. The development of regioselective conditions for these different transformations yielded the synthesis of 4-amino-2,6,8-trisubstituted pyrido[3,2-d]pyrimidine derivatives, with various substituents.     

Improved Synthesis of Indirubin Derivatives by Sequential Build‐Up of the Indoxyl Unit: First Preparation of Fluorescent Indirubins

Indirubin, present in extracts of Isatis tinctoria and some other plant species, has promising cytotoxicity against a variety of cell lines by inhibition of cyclin‐dependent kinases. Chemical synthesis of its derivatives relies on the combination of isatins and 2,3‐dihydro‐1H‐indol‐3‐one (‘indoxyl’) derivatives and usually yields indigo as well as other by‐products. Inspection of the hydrolysis of the long‐known condensation products of 2‐thioxothiazolidin‐4‐one with isatins gave useful hints for an improved synthesis of indirubins: this reaction does not yield quinoline derivatives but 2‐(2,3‐dihydro‐2‐oxo‐1H‐indol‐3‐ylidene)‐2‐sulfanyl acetic acids. By substitution of the sulfanyl group in this oxindoles with anilines and straightforward cyclization under Nazarov conditions, a broad variety of indirubins substituted in the indoxyl ring system are thus available, usually in very good purity and yield. Use of naphthylamines in this reaction sequence yields various fluorescent substances with λ_fl at ca. 630 nm.