Functionalized 1,3-dienes are ubiquitous structural motifs in biologically pertinent molecules. They are frequently employed as precursors for a broad range of chemical transformations, including Diels-Alder reactions. The stereoselective construction of highly decorated 1,3-dienes therefore represents an important research objective. Medicinal chemists are becoming increasingly interested in synthetic methodologies that not only achieve expedient construction and peripheral editing of heterocycles, but also seek to modify their core framework in order to achieve skeletal remodeling. In a succinct manifestation of this \u27scaffold hopping\u27 concept, we herein describe a cascade reaction, which converts thiomorpholinone-tethered alkenoic acids to 1,1-disubstituted amino-1,3-dienes. This domino process involves esterification of the acid, base-assisted ring-opening, and concomitant 1,2-migration of the alpha-amino alkenyl group. Several control experiments have revealed that the alkenyl substituent is necessary for deconstruction to occur. Inherently more activated N-aryl-substituted thiomorpholinone acids react significantly faster than their less activated N-alkyl congeners

Beng, Timothy K.

Borg, Claire

Farah, Abdikani Omar

Garcia, Jorge

ScholarWorks at Central Washington University

Central Washington University ScholarWorks@CWU Student Published Works Student Scholarship and Creative Works 1-23-2023 Serendipitous synthesis of cross-conjugated dienes by cascade deconstructive esterification of thiomorpholinone-tethered alkenoic acids Abdikani Omar Farah Jorge Garcia Claire Borg Timothy K. Beng Follow this and additional works at: https://digitalcommons.cwu.edu/studentarticles  Part of the Chemistry Commons Serendipitous synthesis of cross-conjugated dienesby cascade deconstructive esterification ofthiomorpholinone-tethered alkenoic acids†Abdikani Omar Farah, Jorge Garcia, Claire Borg and Timothy K. Beng *Functionalized 1,3-dienes are ubiquitous structural motifs in biologically pertinent molecules. They arefrequently employed as precursors for a broad range of chemical transformations, including Diels–Alderreactions. The stereoselective construction of highly decorated 1,3-dienes therefore represents animportant research objective. Medicinal chemists are becoming increasingly interested in syntheticmethodologies that not only achieve expedient construction and peripheral editing of heterocycles, butalso seek to modify their core framework in order to achieve skeletal remodeling. In a succinctmanifestation of this ‘scaffold hopping’ concept, we herein describe a cascade reaction, which convertsthiomorpholinone-tethered alkenoic acids to 1,1-disubstituted amino-1,3-dienes. This domino processinvolves esterification of the acid, base-assisted ring-opening, and concomitant 1,2-migration of the a-amino alkenyl group. Several control experiments have revealed that the alkenyl substituent is necessaryfor deconstruction to occur. Inherently more activated N-aryl-substituted thiomorpholinone acids reactsignificantly faster than their less activated N-alkyl congeners.Functionalized 1,3-dienes are omnipresent scaffolds in biolog-ically pertinent molecules and also feature as precursors fora broad range of chemical transformations.1 Examples includemetathesis, ene reactions, reductive aldolization, or cycloaddi-tion. Specically, the increased reactivity of amino-substituted1,3-dienes in the heteroatom-assisted Diels–Alder reactionallows for the facile preparation of functional arrays, whichwould otherwise be difficult to obtain through conventionalmodes of reactivity.2 Indeed, bimolecular and intramolecularDiels–Alder reactions of 1-N-acylamino-1,3-dienes have beenwell-studied and typically proceed with a high degree of regio-selectivity and facial selectivity.3 It is now fully appreciated thatthe alkene geometry inuences the stereochemical outcomeand the efficiency of reactions involving 1,3-dienes.4 Hence,several synthetic methods have been developed for the stereo-selective construction of substituted 1,3-dienes.5Sulfur-containing compounds are highly prevalent in naturaland various biological systems.6 The divalent sulfur atomintroduces a metabolic liability from a drug discovery stand-point.7,8 Specically, the 1,4-thiomorpholine moiety has beenwidely encountered in a variety of bioactive products includingDPP-IV inhibitors,9 anti-inammatory drugs,10 anti-mycobacterial agents,11 and hypolipidemic compounds.12–15 Wepreviously revealed that base-assisted methyl esterication of N-alkyl thiomorpholinone acids of type 1 (Fig. 1A) at roomtemperature, followed by Vilsmeier–Haack functionalizationafforded dihydro-1,4-thiazines such as 2.16 During the course ofthe aforementioned studies, when a thiomorpholinone acidFig. 1 (A) Peripheral functionalization of N-alkylated allylic thio-morpholinone acids, (B) serendipitous discovery of a deconstructiveesterification protocol, (C) proposed plan for the synthesis of cross-conjugated aminodienes of type 4.Department of Chemistry, Central Washington University, Ellensburg, WA 98926, USA.E-mail: Timothy.beng@cwu.edu† Electronic supplementary information (ESI) available: Experimental proceduresand spectroscopic data. See DOI: https://doi.org/10.1039/d2ra07916jCite this: RSC Adv., 2023, 13, 3181Received 11th December 2022Accepted 10th January 2023DOI: 10.1039/d2ra07916jrsc.li/rsc-advances© 2023 The Author(s). Published by the Royal Society of Chemistry RSC Adv., 2023, 13, 3181–3185 | 3181RSC AdvancesPAPER This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.View Article OnlineView Journal  | View Issuebearing a bulky tert-butyl group (i.e., 3a), was methylated at 50 °C, the expected lactam ester was not observed. Instead, ring-opened product 4a was obtained (Fig. 1B). Notably, 4acontains the b-enamino ester subunit, which is a well-recognized synthon for accessing azaheterocyclic architecturessuch as indoles, quinolines, pyridinones, and amino-furanones.17 Additionally, 4a harbors the highly versatile N,N-disubstituted-1,3-aminodiene motif.Desiring an expedient and practical approach for accessingcross-conjugated aminodienes of type 4a, as well as to gain a fullunderstanding of the mechanistic underpinnings of the trans-formation, we sought to build on the aforementioned loneexample by examining the scope of deconstructive estericationof thiomorpholinone-tethered alkenoic acids (Fig. 1C). Intrinsicto our design was the prospect of exploiting this cascade reac-tion, given that such domino processes are inherently step andatom-economical. Cascade reactions oen lead to a reductionin the amount of waste and in the number of purication steps.Efforts toward the elicitation of our ideals are described herein.We commenced these studies by benchmarking our opti-mization efforts toward the synthesis of cross-conjugated ami-nodienes with the reaction conditions described in Table 1. Inthe event, using acid 3a, K2CO3 emerged as the most effectivebase and DMF emerged as the solvent of choice.Under these mild conditions, the scope of this cascadeesterication and ring-opening protocol with respect to theorganic bromide was explored. In the event, the differentiallysubstituted b-enaminoates depicted in Scheme 1 were obtained.Benzyl-, allyl-, alkyl-, and propargyl bromides are all competentelectrophiles. The synthesis of ring-closing metathesis-suitabletrienes such as 4d/e/i sets the stage for the late-stage construc-tion of medium- and large-sized lactones.We have explored the scope of this deconstructive esteri-cation protocol with respect to the electronic properties of thealkenyl moiety. Aer noticing that the N-aryl substituted thio-morpholinone acids underwent deconstructive methylationfaster than 3a, the former were used to evaluate the scope. In theevent, we nd that lactam acids harboring both electron-richand electron-decient styrenyl groups react competently(Scheme 2, 4k–r). At present, the synthesis of alkenoic acid 3 islimited to cinnamaldehyde-derived a,b-unsaturated imines,which explains why we have not evaluated other alkene groups.Knowing that the nature of the nitrogen substituent present ona nitrogen-containing compound can have a dramatic effect onits biological activity and reactivity, lactam acids bearing diversearyl substitution on nitrogen have been surveyed (see 4s–y). Theresults show that electronically diverse N-aryl substituents areamenable to this deconstructive esterication protocol. Addi-tionally, ortho-substituted aryl moieties can be installed (see 4t).The incorporation of a uorinated moiety (see 4o) generallyincreases the solubility, lipophilicity, and metabolic stability ofthe parent molecules, thus, explaining why ∼25% of existingpreclinical drugs and 40% of agrochemicals contain at least oneuorine atom.18 Specically, the CF3 group enjoys a privilegedrole because its incorporation oen enhances efficacy bypromoting electrostatic interactions with targets, improvingcellular membrane permeability, and increasing robustnesstoward oxidative metabolism of the drug.19 It is thereforenoteworthy that diene 4u, which bears a CF3 group, is obtain-able in good yield. Simultaneous variation of the N-arylsubstituent and the styrenyl unit has also been achieved (see 4z–z3).21 Iodoarylated substituents are well tolerated in this trans-formation (see 4x, 4y, and 4z3), which bodes well for late-stageTable 1 Optimization of the deconstructive functionalization of allylicthiomorpholinone acid 3aEntry Deviation from conditions A% Yieldof 4a1 Tetrahydrofuran (THF) as solvent 662 2-Methyltetrahydrofuran (2-MeTHF) as solvent 703 Acetonitrile (MeCN) as solvent 524 N,N-Dimethylacetamide (DMA) as solvent 735 DMSO as solvent 596 Na2CO3 in place of K2CO3 757 Cs2CO3 in place of K2CO3 708 CsF in place of K2CO3 599 NaHCO3 in place of K2CO3 3810 KHCO3 in place of K2CO3 5711 Aer 48 h at room temperature 28Scheme 1 Deconstructive esterification of allylic thiomorpholinoneacid 3a with various organic bromides.3182 | RSC Adv., 2023, 13, 3181–3185 © 2023 The Author(s). Published by the Royal Society of ChemistryRSC Advances Paper This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.View Article Onlinediversication given that the iodo group is an excellent requisitegroup for cross-coupling purposes.20A plausible mechanism for the deconstructive esterication,which takes advantage of the relatively weak C–S bond, involvesbase-assisted O-methylation of 3b to arrive at 5, whichundergoes base-assisted elimination to furnish 6 (Fig. 2). Thecascade process continues with concomitant 1,2-styryl migra-tion to afford the 1,3-diene (i.e., 4a), following aqueous workup.Some mechanistically intuitive experiments have revealedthat N-aryl-substituted thiomorpholinone acids bearing inter-nally trisubstituted styrenes are not amenable to base-mediatedring-opening at room temperature (Scheme 3, see 8a/b).However, a thiomorpholinone-tethered externally trisubstitutedalkenoic acid does undergo successful deconstructive methyl-ation (see 4z4). We attribute the failure to observe ring-openingin 8a/b to steric encumbrance imposed by the methyl group,Scheme 2 Scope of deconstructive methylesterification of allylicthiomorpholinone acids.Fig. 2 Proposed pathway for the deconstructive esterification(substrate 3b is chosen for simplicity).Scheme 3 Control experiments on the methylesterification of diversethiomorpholinone acids.© 2023 The Author(s). Published by the Royal Society of Chemistry RSC Adv., 2023, 13, 3181–3185 | 3183Paper RSC Advances This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.View Article Onlinewhich is closer to the reactive center. In the case of 4z4,although the additional phenyl group is sterically moreimposing than a methyl group, it is positioned further awayfrom the reactive site. The sensitivity of the deconstructiveesterication to steric congestion is further highlighted by theobservation that no ring-opening occurs when the alkenyl groupresident in 3b is replaced by an electronically more suitable arylgroup (see 10a). An alkyl-substituted thiomorpholinone doesnot undergo ring-opening (see 10b), probably because in thiscase, the a-amino proton is not acidic enough for deprotonationby K2CO3.In summary, versatile cross-conjugated thiol-bearing ami-nodienes have been prepared in a stereocontrolled andmodularmanner, by engaging thiomorpholinone-tethered alkenoicacids in a cascade process featuring esterication, base-mediated ring opening and concomitant 1,2-styryl migration.Whereas N-arylated allylic thiomorpholinones readily undergodeconstructive esterication, the less activated N-alkylatedcongeners are less charitable substrates and require heating to50 °C. The C6-alkenyl substituent is necessary for ring-openingto occur. However, the deconstructive esterication is quitesensitive to the stereoelectronic properties of the alkene. Theinterrogation of 4 in Diels–Alder reactions as well as the eval-uation of their leishmanicidal activities are underway.Author contributionsA. O. F. – investigation, data curation, validation; J. G. – inves-tigation, methodology; C. B. – investigation, methodology; T. K.B. – conceptualization, project administration, investigation,supervision, writing – original dra, funding acquisition.Conflicts of interestThere are no conicts of interest to declare.AcknowledgementsWe are grateful to Central Washington University for nancialsupport through startup funds to T. K. B. The School of Grad-uate Studies and Research is thanked for partial support of thiswork through a Faculty Research Award to T. K. B. and a grad-uate fellowship to A. O. F. Provost DenBeste is thanked forresearch fellowships to J. G. and C. B.Notes and references1 (a) W. C. White, Chem.-Biol. Interact., 2007, 166, 10–14; (b)G. Evano, N. Blanchard and M. Toumi, Chem. Rev., 2008,108, 3054–3131; (c) M. S. McCammant, L. Liao andM. S. Sigman, J. Am. Chem. Soc., 2013, 135, 4167–4170; (d)Q.-A. Chen, D. K. Kim and V. M. Dong, J. Am. Chem. Soc.,2014, 136, 3772–3775; (e) Y. 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Chem., 2020, 44, 4257–4261.21 The synthesis of alkenoic acid 3 using the 1,3-azadiene-anhydride reaction is currently limited to N-alkyl- and N-aryl-a,b-unsaturated imines. Strongly electron-withdrawingN-substituents such as N-Boc- and N-Cbz-a,b-unsaturatedimines are not tolerated. See H. Braunstein, S. Langevin,M. Khim, J. Adamson, K. Hovenkotter, L. Kotlarz,B. Mansker and T. K. Beng, Org. Biomol. Chem., 2016, 14,8864–8872.© 2023 The Author(s). Published by the Royal Society of Chemistry RSC Adv., 2023, 13, 3181–3185 | 3185Paper RSC Advances This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.View Article Online

Serendipitous synthesis of cross-conjugated dienes by cascade deconstructive esterification of thiomorpholinone-tethered alkenoic acids

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Serendipitous synthesis of cross-conjugated dienes by cascade deconstructive esterification of thiomorpholinone-tethered alkenoic acids

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