1,4-Dithianes: attractive C2-building blocks for the synthesis of complex molecular architectures

• Bram Ryckaert,
• Ellen Demeyere,
• Frederick Degroote,
• Hilde Janssens and
• Johan M. Winne

Beilstein J. Org. Chem. 2023, 19, 115–132, doi:10.3762/bjoc.19.12

• (hetero)aromatic building blocks. 1,4-Dithianes have as yet not been investigated to the same extent as their well-known 1,3-dithiane counterparts, but they do offer attractive transformations that can find good use in the assembly of a wide array of complex molecular architectures, ranging from lipids

• , and several excellent reviews have highlighted their synthetic versatility and utility in the assembly of complex target molecules [4][5][6]. Some recent examples of 1,3-dithiane-mediated short and efficient total syntheses of complex target products are shown in Scheme 1b [7], wherein the original

• ‘dithiane-scaffolding’ is indicated on the structures of the final targets. Compared to the very accomplished 1,3-dithianes, not many other sulfur-heterocycles have been able to follow into the mainstream organic synthesis tool box. For example, 1,3-dithiolanes are underperforming as heterocyclic building

Synthetic study toward tridachiapyrone B

• Morgan Cormier,
• Florian Hernvann and
• Michaël De Paolis

Beilstein J. Org. Chem. 2022, 18, 1741–1748, doi:10.3762/bjoc.18.183

• chiral tetrahydrofuran (Scheme 1b). To assemble the skeleton of the natural product, we developed a new strategy in which the α,α’-dimethoxy-γ-pyrone motif 2 was first desymmetrized by a sequence encompassing the conjugate addition of 2-lithio-1,3-dithiane, elimination of methoxide lithium, and

• deprotonation of 2-(α’-methoxy-γ-pyrone)-1,3-dithiane. The resulting vinylogous enolate intermediate was trapped with the electrophile 3, amounting to the one-pot preparation of compound 4, having a masked carbonyl function connecting both key fragments [27][28]. Isolated and characterized by Schmitz [17], the

• temperature in contrast with the nucleophile 2-lithio-1,3-dithiane, and with acetic acid as electrophile (Scheme 3). Among the possible isomers that can be expected, a single one 6a’ was isolated in 49% yield after trituration, as it was found rather unstable on silica gel. While the addition of more reactive

Total synthesis of grayanane natural products

• Nicolas Fay,
• Rémi Blieck,
• Cyrille Kouklovsky and
• Aurélien de la Torre

Beilstein J. Org. Chem. 2022, 18, 1707–1719, doi:10.3762/bjoc.18.181

• a TBS ether, α,β-desaturation, dithiane addition, MOM protection and dithiane deprotection. The fragment 25 was lithiated with t-BuLi and the fragment 29 was then added, forming the coupling product as a 5:5:1:1 separable mixture of diastereomers (Scheme 5). The desired diastereomer 30 was isolated

Synthetic strategies toward 1,3-oxathiolane nucleoside analogues

• Umesh P. Aher,
• Dhananjai Srivastava,
• Girij P. Singh and
• Jayashree B. S

Beilstein J. Org. Chem. 2021, 17, 2680–2715, doi:10.3762/bjoc.17.182

• diastereomers by silica gel column chromatography and reaction with lead tetraacetate provided the key oxathiolane derivative 31. In 1995, Jin et al. [46] carried out the reaction of 1,4-dithiane-2,5-diol (3q) with glyoxylic acid (3g) hydrate at reflux temperature in tert-butyl methyl ether, which provided the

• acid derivatives to test the impact of a chiral auxiliary on N-glycosylation. Compound 50 was synthesized by ozonolysis of alkene 3rb, followed by reaction of aldehyde (generated in situ from alkene) with 1,4-dithiane-2,5-diol (3q). The use of lactic acid derivatives provided both enantiomers of

• highly effective crystallization-induced DKR to achieve an efficient synthesis of enantiomerically pure oxathiolane-based lactol 56a from ʟ-menthyl glyoxylate (3h) monohydrate and 1,4-dithiane-2,5-diol (3q, Scheme 17). The investigation proved that the base TEA was capable of effecting the equilibration

Synthetic approaches to bowl-shaped π-conjugated sumanene and its congeners

• Shakeel Alvi and
• Rashid Ali

Beilstein J. Org. Chem. 2020, 16, 2212–2259, doi:10.3762/bjoc.16.186

• benzylic positions of sumanene in a two-step approach to generate hexafluorosumanene 55 in an overall good yield [44]. As can be seen from an inspection of Scheme 12, they first prepared cyclic dithiane 54 from trisumanenone 40 using propanedithiol in the presence of BF3 since dithianes are outstanding

Syntheses of spliceostatins and thailanstatins: a review

• William A. Donaldson

Beilstein J. Org. Chem. 2020, 16, 1991–2006, doi:10.3762/bjoc.16.166

• ), low yield (5.4%), and the relative expense of the starting material ($22.3/g). In their second-generation approach (Scheme 11) [9], the acetonide-protected dithiane was alkylated according to Horton’s procedure [34]. A deprotection and cyclic-ketal formation gave 70, allowing for a convergence with

• reaction/hydrolysis sequence. The use of the dithiane 80 protecting group was crucial for the following steps. Initial attempts of using a dioxolane protecting group for the C-1 ketone (instead of dithiane) led to an insurmountable difficulty of the selective hydrolysis of the dioxolane and acetonide

• removal of the dithiane protecting group and the cyclic-ketal formation gave 84. The oxidative hydrolysis of the PMB ether and the reaction with mCPBA afforded the epoxide 85. While relatively short (9 steps), the nonstereoselective formation of 81a/b led to a lower overall yield. Syntheses of the C-1–C-6

Recent synthesis of thietanes

• Jiaxi Xu

Beilstein J. Org. Chem. 2020, 16, 1357–1410, doi:10.3762/bjoc.16.116

• retention and inversion products [63] (Scheme 38). However, some olefins, such as cyclohexene, oct-1-ene, vinyl ether, vinyl sulfide, etc., produced 1,4-dithiane derivatives as products through the reaction of two molecules of thiobenzophenone (184a) and one molecule of the olefin under irradiation with 589

Electrophilic oligodeoxynucleotide synthesis using dM-Dmoc for amino protection

• Shahien Shahsavari,
• Dhananjani N. A. M. Eriyagama,
• Bhaskar Halami,
• Vagarshak Begoyan,
• Marina Tanasova,
• Jinsen Chen and
• Shiyue Fang

Beilstein J. Org. Chem. 2019, 15, 1116–1128, doi:10.3762/bjoc.15.108

• electrophilic oligodeoxynucleotides (ODNs) was achieved using dimethyl-Dmoc (dM-Dmoc) as amino protecting group. Due to the high steric hindrance of the 2-(propan-2-ylidene)-1,3-dithiane side product from deprotection, the use of excess nucleophilic scavengers such as aniline to prevent Michael addition of the

• steps from 1,3-dithiane (6) according to a procedure we reported previously [44]. The dC phosphoramidite monomer 3a was synthesized from compound 9 [45]. The formation of the hindered O-tert-alkyl N-arylcarbamate 10 was found highly challenging [44][46][47]. We tried many conditions and finally found

• not caused by premature oxidation of the dM-Dmoc groups by iodine in the oxidation step in ODN synthesis because the problem did not exist when Dmoc was used for ODN synthesis [41]. In addition, we also subjected 1,3-dithiane to the iodine oxidation conditions for over 24 hours, no oxidation could be

An amine protecting group deprotectable under nearly neutral oxidative conditions

• Shahien Shahsavari,
• Chase McNamara,
• Mark Sylvester,
• Emily Bromley,
• Savannah Joslin,
• Bao-Yuan Lu and
• Shiyue Fang

Beilstein J. Org. Chem. 2018, 14, 1750–1757, doi:10.3762/bjoc.14.149

• 10.3762/bjoc.14.149 Abstract The 1,3-dithiane-based dM-Dmoc group was studied for the protection of amino groups. Protection was achieved under mild conditions for aliphatic amines, and under highly reactive conditions for the less reactive arylamines. Moderate to excellent yields were obtained

• carboxylic acid protection [19]. To further explore the use of the 1,3-dithiane function as protecting group in organic synthesis, here we report the results of our studies on the use of the dimethyl-1,3-dithian-2-ylmethoxycarbonyl (dM-Dmoc) group for amine protection (Scheme 1). Compared with the Dmoc group

• of Dmoc due to its higher steric hindrance. Such side reactions could be a serious issue in some situations [18]. Results and Discussion To protect amines, compound 4 was prepared readily by reacting deprotonated 1,3-dithiane with acetone followed by treating with p-nitrophenylchloroformate (see

Synthesis of chiral 3-substituted 3-amino-2-oxindoles through enantioselective catalytic nucleophilic additions to isatin imines

• Hélène Pellissier

Beilstein J. Org. Chem. 2018, 14, 1349–1369, doi:10.3762/bjoc.14.114

• asymmetric formal [3 + 2] annulation reaction between N-Boc-isatin imines 3 and 1,4-dithiane-2,5-diol (53) as equal equivalent of 2-mercaptoacetaldehyde [78]. The domino reaction catalyzed by chiral tertiary amine-squaramide catalyst 54 began with the addition of 2-mercaptoacetaldehyde to isatin imine 3

• cinchona alkaloid-derived thiourea. Aza-Henry reaction of N-Boc-isatin imines with nitromethane catalyzed by a bifunctional guanidine. Domino addition/cyclization reaction of N-Boc-isatin imines with 1,4-dithiane-2,5-diol (53) catalyzed by a tertiary amine-squaramide. Nickel-catalyzed additions of methanol

A selective removal of the secondary hydroxy group from ortho-dithioacetal-substituted diarylmethanols

• Anna Czarnecka,
• Emilia Kowalska,
• Agnieszka Bodzioch,
• Joanna Skalik,
• Marek Koprowski,
• Krzysztof Owsianik and
• Piotr Bałczewski

Beilstein J. Org. Chem. 2018, 14, 1229–1237, doi:10.3762/bjoc.14.105

• % yields and is recommended for the substrates containing sulfur atoms, for which transition metal-induced reactions fail. Keywords: diarylmethanes; diarylmethanols; 1,3-dithiane; selective reduction; sodium cyanoborohydride; zinc iodide; Introduction In last decades, diarylmethanes, such as I–IV and

• -coupling reactions of substrates containing an 1,3-dithiane moiety are feasible, like in the case of the 2-arylation of 2-aryl-substituted 1,3-dithianes. However, in the case of 2-benzyl-substituted 1,3-dithianes, a tandem elimination/1,3-dithiane ring opening followed by a Pd-catalyzed C−S bond formation

Addition of dithi(ol)anylium tetrafluoroborates to α,β-unsaturated ketones

• Yu-Chieh Huang,
• An Nguyen,
• Simone Gräßle,
• Sylvia Vanderheiden,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2018, 14, 515–522, doi:10.3762/bjoc.14.37

• dithiolanes by addition of an ynone to α-alkyl or aryl-substitued dithiolanylium TFBs. Keywords: addition to α,β-unsaturated carbonyls; dithiane chemistry; dithianylium tetrafluoroborate (TFB); ketene dithiane; Introduction 1,3-Dithioacetals are a common motif in organic chemistry. They are part of

• dithiolane and dithiane protecting groups which are irreplaceable intermediates for the introduction of, e.g., fluorine via gem-difluorination [1][2]. They also allow the formation of valuable building blocks that can be used for diverse transformations in organic chemistry (e.g., Umpolung) [3]. Ketene 1,3

• position R1 are possible and result in the isolation of 4a–5h in up to very good yields (entries 1–8, Table 1). The only exception is compound 5e, which could not be obtained due to the influence of the sterically bulky iPr group of the electrophile 3e. The conversion of dithiane 2a with electrophile 3e

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

• Françoise Debart,
• Christelle Dupouy and
• Jean-Jacques Vasseur

Beilstein J. Org. Chem. 2018, 14, 436–469, doi:10.3762/bjoc.14.32

• within a robust cyclic disulfide moiety [14]. Several modified ONs containing the cyclic disulfide trans-5-benzyl-1,2-dithiane-4-yl moiety have been synthesized using the corresponding thymidine phosphoramidite. Although they exhibited strong stability in serum and penetrated cells more efficiently

A novel application of 2-silylated 1,3-dithiolanes for the synthesis of aryl/hetaryl-substituted ethenes and dibenzofulvenes

• Grzegorz Mlostoń,
• Paulina Pipiak,
• Róża Hamera-Fałdyga and
• Heinz Heimgartner

Beilstein J. Org. Chem. 2017, 13, 1900–1906, doi:10.3762/bjoc.13.185

• some dihetaryl thioketones, e.g., 1d and 1e, were reported [22]. In contrast to CH2N2, TMS-CHN2 reacted with thiobenzophenone (1a) with evolution of N2 even at −75 °C and led to a mixture of 4,4,5,5-tetraphenyl-1,3-dithiolane 6a and 2,2,3,3-tetraphenyl-1,4-dithiane 7 (Scheme 2). This result

• the reagents in a ratio of 3:1. Under these conditions, 1,3-dithiolane 6a was formed almost exclusively with only traces of 1,4-dithiane 7 as revealed by 1H NMR analysis of the crude reaction mixture. Desilylation of 6a occurred quantitatively and the known tetraphenylethylene (9a) [26] was obtained

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

Phosphazene-catalyzed desymmetrization of cyclohexadienones by dithiane addition

• Matthew A. Horwitz,
• Elisabetta Massolo and
• Jeffrey S. Johnson

Beilstein J. Org. Chem. 2017, 13, 762–767, doi:10.3762/bjoc.13.75

• Matthew A. Horwitz Elisabetta Massolo Jeffrey S. Johnson Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290, USA 10.3762/bjoc.13.75 Abstract We report a desymmetrization of cyclohexadienones by intramolecular conjugate addition of a tethered dithiane

• ; desymmetrization; dithiane; iminophosphoranes; organocatalysis; phosphazenes; Findings Desymmetrization has become a well-developed strategy for the construction of complex molecular frameworks [1][2][3][4][5][6]. Cyclohexadienones are multipurpose synthetic building blocks that have found a central role in

• reduction of prochiral cyclohexadienones using copper hydride generated in situ [23]. Inspired by these advances, we sought to develop an alternative and complementary method invoking the dithiane moiety as an established and easily accessible glyoxylate anion surrogate [24][25][26][27][28][29]. This would

Effect of the ortho-hydroxy group of salicylaldehyde in the A³ coupling reaction: A metal-catalyst-free synthesis of propargylamine

• Sujit Ghosh,
• Kinkar Biswas,
• Suchandra Bhattacharya,
• Pranab Ghosh and
• Basudeb Basu

Beilstein J. Org. Chem. 2017, 13, 552–557, doi:10.3762/bjoc.13.53

• in developing new organic reaction methodologies as well as to synthesize propargylamine, we performed one reaction of salicylaldehyde, morpholine and phenylacetylene at 80 °C in the presence of a Cu(I) dithiane-based complex as the catalyst that gave rise to the formation of 3a in good yield (89

Dimerization reactions of aryl selenophen-2-yl-substituted thiocarbonyl S-methanides as diradical processes: a computational study

• Michael L. McKee,
• Grzegorz Mlostoń,
• Katarzyna Urbaniak and
• Heinz Heimgartner

Beilstein J. Org. Chem. 2017, 13, 410–416, doi:10.3762/bjoc.13.44

• computational methods. The preferred formation of the unusual macroheterocycle, competitive with the 1,3-ring closure leading to a thiirane and the head-to-head dimerization yielding a 1,4-dithiane derivative, respectively, was explained based on the analysis of the structure of the favored conformer of the

• Supporting Information File 1, Table SI1) in the broken symmetry solution. The further conversion of the conformers of the intermediate diradical 12 into the macroheterocycle 9, the six-membered 1,4-dithiane 13, and the ten-membered heterocycle 14, respectively, is governed by two factors: the unpaired spin

• -diradical with a very small enthalpic barrier (2.5 kcal/mol). The cyclization of this intermediate resulting in the formation of the six-membered 1,4-dithiane is a low energy process, which requires a free energy of only 15.3 kcal/mol. This value is significantly lower than in the studied case of the

Diradical reaction mechanisms in [3 + 2]-cycloadditions of hetaryl thioketones with alkyl- or trimethylsilyl-substituted diazomethanes

• Grzegorz Mlostoń,
• Paulina Pipiak and
• Heinz Heimgartner

Beilstein J. Org. Chem. 2016, 12, 716–724, doi:10.3762/bjoc.12.71

• total, equimolar amount of 7c. After warming up and typical work-up procedure, the corresponding 1,3-dithiolane 10o and 1,4-dithiane 4c in a ratio of 2:1 were found as products identified in the 1H NMR spectrum of the crude reaction mixture. Thus, in this reaction dimerization of the intermediate

Stereoselective amine-thiourea-catalysed sulfa-Michael/nitroaldol cascade approach to 3,4,5-substituted tetrahydrothiophenes bearing a quaternary stereocenter

• Sara Meninno,
• Chiara Volpe,
• Giorgio Della Sala,
• Amedeo Capobianco and
• Alessandra Lattanzi

Beilstein J. Org. Chem. 2016, 12, 643–647, doi:10.3762/bjoc.12.63

• nitroalkenes and commercially available 1,4-dithiane-2,5-diol to 3,4,5-substituted tetrahydrothiophenes, bearing a quaternary stereocenter, is presented. A secondary amine thiourea derived from (R,R)-1,2-diphenylethylamine was found to be the most effective catalyst when using trans-β-methyl-β-nitrostyrenes

• report on a dynamic system combining a 1,1,3,3-tetramethylguanidine (TMG)/ZnI2-catalyzed diastereoselective cascade sulfa-Michael/nitroaldol reaction followed by lipases catalyzed kinetic resolution using two representative trans-β-methyl-β-nitrostyrenes and 1,4-dithiane-2,5-diol as reagents [21]. One

• [22] with 1,4-dithiane-2,5-diol. Based on all above considerations and prompted by our interest in asymmetric synthesis of functionalized tetrahydrothiophenes [14], we wondered whether we could use bifunctional organocatalysts to develop a diastereo- and enantioselective cascade sulfa-Michael

An efficient synthesis of N-substituted 3-nitrothiophen-2-amines

• Sundaravel Vivek Kumar,
• Shanmugam Muthusubramanian,
• J. Carlos Menéndez and
• Subbu Perumal

Beilstein J. Org. Chem. 2015, 11, 1707–1712, doi:10.3762/bjoc.11.185

• , 28040 Madrid, Spain 10.3762/bjoc.11.185 Abstract A novel protocol for the synthesis of 3-nitro-N-aryl/alkylthiophen-2-amines in good yields from the reaction of α-nitroketene N,S-aryl/alkylaminoacetals and 1,4-dithiane-2,5-diol in the presence of K2CO3 in refluxing ethanol is described. This

• associated with the lack of regioselectivity and difficult isomer separation [23]. Other methods for the synthesis of 2,3-disubsituted thiophenes include the reactions of (i) 1,4-dithiane-2,5-diol with nitroalkenes [24], activated nitriles [25] and cyanoacetamide [26]; (ii) 3-nitrothiophene with Grignard

• goals of green chemistry [32]. In this context, we wish to report herein a new and efficient synthesis of 3-nitro-N-aryl/alkylthiophen-2-amines based on domino reactions between α-nitroketene N,S-aryl/alkylaminoacetals and 1,4-dithiane-2,5-diol, the dimer of 2-mercaptoacetaldehyde (Scheme 2). This work

Thiazole formation through a modified Gewald reaction

• Carl J. Mallia,
• Lukas Englert,
• Gary C. Walter and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 875–883, doi:10.3762/bjoc.11.98

• The synthesis of thiazoles and thiophenes starting from nitriles, via a modified Gewald reaction has been studied for a number of different substrates. 1,4-Dithiane-2,5-diol was used as the aldehyde precursor to give either 2-substituted thiazoles or 2-substituted aminothiophenes depending on the

• substitution of the α-carbon to the cyano group. Keywords: design of experiment (DOE); 1,4-dithiane-2,5-diol; Gewald reaction; thiazole; thiophene; Introduction Thiazoles are privileged motifs which are encountered in many naturally occurring bioactive compounds and pharmaceuticals with indications in a

• an effecient way of synthesising 2-subsituted thiazoles from readily available, air stable 1,4-dithiane-2,5-diol (10) as a precursor for 2-mercaptoacetaldehyde. Experimental See Supporting Information File 1 for full experimental data. Selected examples of biologically active thiazole containing

Sacrolide A, a new antimicrobial and cytotoxic oxylipin macrolide from the edible cyanobacterium Aphanothece sacrum

• Naoya Oku,
• Miyako Matsumoto,
• Kohsuke Yonejima,
• Keijiroh Tansei and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2014, 10, 1808–1816, doi:10.3762/bjoc.10.190

• because of epimerization [12]. To circumvent this problem, we initially attempted to protect the ketone group prior to chemical conversion (Scheme 1). Compound 1 was acetylated (Supporting Information File 1) and subjected to protection as 1,3-dithiane [13] or 1,4-dinitrophenylhydrazone [14]; however

Asymmetric total synthesis of a putative sex pheromone component from the parasitoid wasp Trichogramma turkestanica

• Danny Geerdink,
• Jeffrey Buter,
• Teris A. van Beek and
• Adriaan J. Minnaard

Beilstein J. Org. Chem. 2014, 10, 761–766, doi:10.3762/bjoc.10.71

• 10 over two steps [23]. As an alternative deoxygenation procedure, we relied on the so-called Mozingo reduction. Although the procedure for dithiane formation has been reported to be catalytic in Lewis acid, we found a linear correlation between the amount of BF3·Et2O used and the conversion (Scheme

Garner’s aldehyde as a versatile intermediate in the synthesis of enantiopure natural products

• Mikko Passiniemi and
• Ari M.P. Koskinen

Beilstein J. Org. Chem. 2013, 9, 2641–2659, doi:10.3762/bjoc.9.300

• higher catalyst loading (5% instead of the usual 3%). Fujisawa studied the addition of lithiated dithiane to (S)-1 (Scheme 13) [66]. Without additives the reaction in THF provided alcohols 27 and 28 in a 7:3 ratio (anti/syn). Addition of aggregation braking HMPT slightly improved the selectivity (10:3

• co-ordinated delivery of the vinyl nucleophile. (a) PhMgBr, THF, −78 °C → 0 °C [62] or (a) PhMgBr, Et2O, 0 °C [63]. (a) cat. RhCl3·3H2O, cat. 26, NaOMe, Ph-B(OH)2, aq DME, 80 °C (24, 71%); (b) cat. RhCl3·3H2O, cat. 26, NaOMe, C6H13CH=CH2-B(OH)2, aq DME, 55 °C (25, 78%). Lithiated dithiane (3 equiv