Base-Mediated Rearrangement of α-Dithioacetyl Propargylamines via Expansion of Dithioacetyl Ring: Synthesis of Medium-Sized S,S-Heterocycles

Base-mediated rearrangement of 1,3-dithianyl-substituted propargylamines in DMF via expansion of the dithiane ring has been reported. The rearrangement provided 9-membered amino-functionalized sulfur-containing heterocycles (dithionine derivatives) in good yields under mild conditions. Propargylamines bearing 5-membered 1,3-dithiolane and 7-membered 1,3-dithiepane rings rearranged in a similar manner yielding 8- and 10-membered S,S-heterocycles, respectively.

S ulfur-containing heterocycles are of particular interest in organic synthesis since they are widely present in pharmaceuticals, agrochemicals, natural products, and organic electronic materials. 1a,b Although thiophene and 5-and 6membered S-heterocycles are the most encountered units in biologically active compounds, medium-sized sulfur rings with extra heteroatoms and amino substituents are essential structural components of several US FDA-approved drugs, pharmaceutically relevant molecules, and natural compounds ( Figure 1). 2a−d On the other hand, construction of mediumsized rings via intramolecular cyclization reactions is more challenging due to unfavorable transannular interactions and torsional strains. 3a−c Several methods are frequently applied for the synthesis of medium-size ring structures such as metalcatalyzed 4a,b or -mediated cyclization reactions, 5 ring-closing metathesis, 6 radical cyclization, 7 and ring-expansion reactions. 8a−d 1,3-Dithiane derivatives are valuable tools that have long been employed in organic synthesis as acyl anion equivalents and as a protecting group for carbonyl compounds. They are also valuable precursors for the synthesis of sulfur-containing acyclic compounds and heterocycles. 1,3-Dithianes have been converted into S,S-heterocycles of various sizes (between 7and 11-membered), generally by following two different routes (Scheme 1). In the first one, dithiane derivatives bearing a leaving group on their side chain undergo ring expansion via Scheme 1. Different Routes for Expansion of the 1,3-Dithiane Ring initially formed bicyclic sulfonium ion and succeeding thionium intermediates. After elimination of a proton in these intermediates, the reaction affords, in general, simple S,Sheterocyclic products lacking functional groups as a mixture of stereoisomers. 9a−c Depending on the presence of a nucleophile in the medium, the thionium ion is trapped to form the ring without a double bond. 10a,b In the second route, 2-alkyl-2-aryl-1,3-dithianes undergo ring expansion with various electrophiles, resulting in 7-membered dithiepine derivatives through formation of a thionium intermediate. 11a,b Functionally substituted dithiepines are accessible based on the amount and type of electrophiles used as well as the substituent on the aryl group. However, to the best of our knowledge, larger rings generated by this method were not reported.
Expansion of the 1,3-dithiane ring was rarely observed under catalytic conditions. 12a−c Propargylic 1,3-dithianes have recently been converted via an Au-catalyzed reaction into 8membered dithio-substituted cyclic allenes (eq 1, Scheme 2a) and dithiocine derivatives (eq 2, Scheme 2a) depending on the type of substituent at the 2 position of the dithiane ring. The reaction mechanism likely involves the formation of a Au− carbene intermediate followed by a 1,2-sulfur shift to produce the cyclic allene. 13 We recently found that electrophilic iodocyclization of 1-(1,3-dithian-2-yl)propargylamines leads to 3-amino-4-iodothiophenes via iodide-induced ring fragmentation of bicyclic sulfonium ion formed as an intermediate product (eq 3, Scheme 2b). 14 During our investigation, we noticed that under strongly basic conditions 1-(1,3-dithian-2yl)propargylamines undergo rearrangement initiated by the abstraction of propagylic proton and followed by expansion of the dithiane ring (eq 4, Scheme 2b). After careful tuning of the reaction conditions, we were able to conduct this transformation using 0.5 equiv of KOtBu in DMF to achieve different substituted amino functionalized 9-membered S,Sheterocycles in good yields.
Initially, heating 1a with 1.0 equiv of KOtBu in DMF at 40°C for 4 h furnished the product 2a in 35% yield. We envisaged that addition of a proton source to the reaction mixture might improve the yield of the products. Thus, varied amounts of H 2 O/tBuOH were added to the reaction mixture at different temperatures. The best yield of the product 2a (71−75%) was obtained with the addition of 1.0 equiv of H 2 O at 40°C with 0.5 equiv of KOtBu as base. Performing the reaction in DMSO as solvent furnished a 65% yield of 2a, while use of THF, CH 3 CN, and CPME did not yield the product. Changing the solvent from DMF to DMA (dimethylacetamide) gave the product in a comparable 76% yield under the optimized conditions. Use of NaOtBu and NaOtAm as base in the reaction in place of KOtBu afforded the product 2a in 70% and 69% yields, respectively, while use of KOH or KHMDS gave a lower yield of the product (Table S1).
As depicted in Scheme 3a, 1,3-dithianyl-substituted propargylamines produced the corresponding 9-membered S,Sheterocycles (dithionine derivatives) 2a−m in good yields (46−84%), irrespective of the electronic properties of aryls on the dithiane ring and on the propargyl moiety. Heteroarylsubstituted propargylamines afforded the dithionines 2n and 2o in 77% and 59% yields, respectively. Propargylamines having amine groups other than morpholine proceeded well under the optimized conditions and gave the corresponding 9membered rings 2p−u in good yields (52−77%). Considering the formation of KOH by combination of KOtBu and water in the reaction medium, we tested 1.0 mmol scale reactions of propargylamines (1a, 1e, 1h, and 1o) with 0.5 mmol of KOH (80%, w/w) under the standard conditions. The reactions Scheme 2. Rearrangement of Propargylic 1,3-Dithianes via Expansion of the Dithiane Ring Scheme 3. Substrate Scope for 8-, 9-, and 10-Membered Rings Organic Letters pubs.acs.org/OrgLett Letter produced the corresponding heterocycles 2a, 2e, 2h, and 2o in good yields, respectively. We performed the reaction of 1o without water to see the reaction performance in the presence of KOH. The reaction gave 2o in 60% yield, similar to the reaction performed with KOtBu. Replacing the aryl group on dithiane with a methyl group resulted in the formation of 8-membered rings 2v and 2y with an exocyclic double bond in 38% yield. The formation of a 9-membered ring structure was not observed in these reactions. To understand the effect of amine group in the reaction, we synthesized a propargyl substituted dithiane derivative 1a 1 without an amine group. Under the standard conditions, this substrate did not yield the 9-membered S,Sheterocycle 2a 1 (Scheme 3b).
Considering the presence of sulfoxide and sulfone moieties in bioactive molecules, oxidation of 2a to the sulfoxide was attempted (Scheme 3c). Reaction of 2a with 2.0 equiv of m-CPBA provided the sulfoxide 3a in 75% yield. However, use of 1.0 equiv of m-CPBA was insufficient for the consumption of 2a, while using more than 2.0 equiv of m-CPBA resulted in a mixture of several unidentifiable compounds. The structure of sulfoxide 3a was unequivocally established by single-crystal Xray structure analysis.
Reactants 4a−e and 6a−d containing the 5-and 7membered dithiolane and dithiepane rings furnished the rearranged products 5a−e and 7a−d, respectively (Scheme 3d,e). Fine tuning of the reaction conditions (see Table S7) was required for the synthesis of 8-membered dithiocine derivatives 5a−e from 1,3-dithiolanyl-substituted propargylamines 4a−e. The best yields were obtained when a solution of KOtBu (2.0 equiv) in DMF was slowly added to the solution of propargylamine at 0°C. This protocol perhaps minimizes the dithiolane ring fragmentation observed in the presence of strong bases. 15a,b Since the reaction gave poor yields when performed without water, we conducted deuterium-labeling experiments to gain insight into the mechanism of the rearrangement reaction. Under the standard conditions, the reaction of 1a yielded dithionine D-2a with 50% deuteration of the methine group when D 2 O was used as a proton source (Scheme 4a). Similarly, 40% D was incorporated into the methine carbon of exocylic double bond in 8-membered ring D-2v (Scheme 4b).
Recently, several reactions, involving the use of strong bases in DMF, DMSO, and DMAc solvents, were proposed to proceed via an electron-transfer mechanism. 16−18 In these reactions, deprotonation of the solvent produces the corresponding anion which was transformed to the carbamoyl radical (from DMF), dimsyl radical (from DMSO), or dimethylcarbamoyl radical (from DMAc) by a subsequent single-electron transfer to the solvent molecule. 16 Furthermore, electron transferred from the carbamoyl, dimsyl, and dimethylcarbamoyl anion to various species such as aryl iodides, aryl methyl sulfones, and benzil derivatives had resulted in the formation of the corresponding radicals. 17 Sliwka et al. showed that the formation of long-lived-radical species by the addition of small quantities of strong bases to DMF and DMSO at room temperature. 18 Since the KOtBu-DMF system was closely linked to the electron-transfer process, we carried out additional control experiments in the presence of radical scavengers (Scheme 4c). The reaction of 1a with 2.0 equiv of TEMPO under the standard conditions produced 2a in 36% yield, which was lower than the optimum yield (75%) of the reaction. On the other hand, the formation of 2a was completely prevented with the addition of 2.0 equiv of BHT (2, and DPPH (2,2-diphenyl-1-picrylhydrazyl radical). The cyclization did not occur in the presence of BHT since it rapidly reacted with KOtBu to form potassium phenoxide. We then tested different amounts of the radical scavengers and p-BQ (p-benzoquinone) in the reaction of 1a with 0.5 and 1.0 equiv of KOtBu under the standard conditions (see Table S8). The reaction was completely suppressed in the presence of 0.20 equiv of DPPH and 0.25 equiv of p-BQ, indicative of the rearrangement following a radical pathway.
Based on the experimental results and the literature precedence, 16 we propose a plausible reaction pathway as depicted in Scheme 4d. 19 The first step involves the deprotonation of DMF by KOtBu, which results in the In summary, a new method based on KOtBu-DMFpromoted rearrangement of dithioacetyl-substituted propargylamines under mild conditions was developed. The rearrangement reaction involves the expansion of the dithioacetal ring and proceeds via an exclusive endo-dig radical cyclization process to afford amino-functionalized S,S-heterocycles of various ring size.

■ ASSOCIATED CONTENT Data Availability Statement
The data underlying this study are available in the published article and its online Supporting Information.