The results reported in this study provide a practical protocol for the construction, in one single step of synthetically important γ-lactones in good yields starting from α-hydroxy cyclobutanone, H2O2 and several stabilized phosphonium ylides. Our synthetic strategy relies on a tandem Baeyer–Villiger oxidation/Wittig reaction/oxa-Michael addition

Barranco S.

Caboni P.

Cuccu F.

Frongia A.

English

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 Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered.  Tandem Baeyer–Villiger/Wittig/oxa-Michael addition: one-step to 5-substituted γ-lactones Stefano Barranco, Federico Cuccu, Pierluigi Caboni and Angelo Frongia*    1   Tetrahedron Letters journal  homepage:  www.elsevier .com   Tandem Baeyer–Villiger/Wittig/oxa-Michael addition: one-step to 5-substituted γ-lactones      Stefano Barranco,a Federico Cuccu,a Pierluigi Cabonib and Angelo Frongiaa,* aDipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Cagliari, Complesso Universitario di Monserrato, S.S. 554, Bivio per Sestu, I-09042, Monserrato, Cagliari, Italy E-mail: afrongia@unica.it  bDipartimento di Scienze della Vita e dell’Ambiente, Università degli Studi di Cagliari, Complesso Universitario di Monserrato-Blocco A, S.S. 554, Bivio per Sestu, I-09042, Monserrato, Cagliari, Italy.  Introduction    γ-Lactones represent an important class of organic compounds which have received considerable attention due to their diverse and interesting biological activities. [1] Several synthetic methods have been reported in the literature for their efficient preparation. [1-8] Among them numerous elegant achievements have been made in the synthesis of 5-(2-oxoalkyl) γ-lactones, including transition-metal catalyzed C−H functionalizations [9-11] and organocatalyzed intramolecular oxa-Michael cyclization cascades. [12-16] Furthermore, tandem oxidation/oxa-Michael addition reaction of 2-alkenylbenzaldehydes [17] and the intramolecular one-pot oxa-Michael reaction of peroxy hemiacetals followed by Kornblum DeLaMare fragmentation [18] have also recently been developed. Over the last few years, our group has explored the reactivity of α‐hydroxy cyclobutanones with electrophiles [19-20] and nucleophiles [21-23] leading to the enantioselective synthesis of other functionalized cyclobutanone derivatives. Hence, further transformations useful for constructing diverse functionalized heterocycles [24-27] and cyclopropane carboxaldehydes [27-29] have also been developed. Continuing with our interest in exploiting new reactivities of α‐hydroxy cyclobutanone and bearing in mind that 5-hydroxydihydrofuran-2(3H)-ones could be used efficiently as substrates in Wittig olefination reactions with stabilized phosphonium ylides (Scheme 1a), [15-16] we wondered whether it was possible to generate γ-lactol 3 (in mixture with its corresponding acyclic oxoacid) in situ from α‐hydroxy cyclobutanone 1 and H2O2 (via a Baeyer-Villiger reaction), and trap it to undergo a tandem Wittig/oxa-Michael addition reaction to access γ-lactones such as 5 (Scheme 1c).  It is worth mentioning that γ-lactol 3 is unstable and its synthesis usually requires tedious multistep procedures (Wermuth-protocol) and/or employ relatively harsh reaction conditions (Scheme 1b). [30-37] On the other hand, tandem- and one-pot reactions incorporating Wittig reagents represent a commonly used strategy in organic synthesis to prepare diverse synthetically useful compounds. [38-39] In particular, oxidation processes carried out in the presence of a Wittig reagent turned out to be an efficient solution to the difficulties of handling carbonyl intermediates labile and/or difficult to isolate. [40-46] Accordingly, the development of new efficient and versatile tandem oxidative procedures is desirable.   Results and discussion  We began our exploration by examining the reaction with α‐hydroxy cyclobutanone 1, phosphonium ylide 2a and ARTICLE  INFO  ABST RACT  Article history: Received Received in revised form Accepted Available online The results reported in this study provide a practical protocol for the construction, in one single step of synthetically important γ-lactones in good yields starting from α‐hydroxy cyclobutanone, H2O2 and several stabilized phosphonium ylides. Our synthetic strategy relies on a tandem Baeyer–Villiger oxidation/Wittig reaction/oxa-Michael addition. 2009 Elsevier Ltd. All rights reserved.         Keywords: γ-Lactones      Baeyer-Villiger Strained rings Tandem reactions Tetrahedron 2 H2O2 (30% aqueous v/v solution) in DMF at room temperature (entry 1).  The proposed tandem reaction occurred with complete consumption of the starting materials and 5-(2-oxo-2-phenylethyl) dihydrofuran-2(3H)-one 5a was obtained in a high conversion (80%) after 48 h along with 6% of the by-product 6a (coming from a hydrogen peroxide-induced oxidative dimerization of phosphonium ylide 2a) [47] and a minor amount of intermediate 4a (14%). Scheme 1. Research background (top and middle panel) and the present work (bottom panel).   Pleasingly, the reaction time was shortened to 24h increasing the reaction temperature to 30°C (79% conversion; entry 2). Further enhancing the temperature to 40°C afforded 5a with a comparable conversion (81%; entry 3). Next, the solvents were briefly investigated and MeCN (entry 4) was found to give a slightly higher conversion (89%) and 70% of isolated yield. The use of other solvents such as toluene, CH2Cl2, 1,4-dioxane, 2-Me-THF and CHCl3 were suitable (entries 5-9), however MeCN remained the preferred choice. Interestingly, in every case examined only trace amount of cyclopropanated 1,4-dicarbonyl 7, coming from a tandem Wittig reaction–ring contraction process were detected. [28] To get insight into the reaction mechanism for the formation of compound 5a, a controlled experiment was performed (Scheme 2). We observed the formation of γ-lactol 3 (a mixture of aldehyde: cyclic hemiacetal forms at a ratio of 64:36% was detected according to the 1H NMR spectrum) reacting 1 with H2O2 in CDCl3 at 40°C after 24 h at room temperature and its subsequent transformation into the corresponding lactone 5a (82%), along with 18% of intermediate 4a, following the addition of phosphonium ylide 2a.  Table 1. Screening of the reaction conditionsa   aReaction conditions: 1 (0.423 mmol; 0.036 g), 2a (0.423 mmol; 0.161 g), H2O2 30% (0.465 mmol; 0.047 mL), solvent (0.32 mL). bDetermined by 1H NMR. cReaction time of 48h. dIsolated yield of 5a in parentheses.  This observation supports our working mechanistic hypothesis proposed in Scheme 1 involving the initial formation of a transient intermediate 3 which subsequently undergoes in a tandem Wittig/oxa-Michael addition reaction to form 5a. The observed formation of 4a during the reaction is also consistent with our proposal.  Scheme 2. Control experiment.    With the optimized conditions in hand, we next sought to evaluate the generality of this reaction using different substituted phosphonium ylides 2. As summarized in Scheme 3, both electron-donating (Me and OMe) and electron-withdrawing (NO2, CF3, CN and OCOMe) substituents in the para or meta position of the aromatic ring of the phosphonium ylide were all compatible with the standard reaction conditions affording the corresponding products 5b-g and 5h-i in good to high yields (54-79%). Similarly, the reaction smoothly proceeded with halogens such as chloro, bromo and fluoro or phenyl at the para-position on the aromatic ring of the phosphonium ylide (5j-m: 67-84% yield) as well as with 1-naphthyl phosphonium ylide 2n (5n: 71% yield). The presence of a bromo in ortho-position resulted in moderate yield (50%) of the corresponding lactone 5o.  entry solvent  temp. °C ratio 5a:4a:6ab 1 DMF RT 80:14:6c 2 DMF 30 79:17:4 3 DMF 40 81:11:8 4 CH3CN 40 89:5:6 (70%) d 5 Toluene 40 74:14:12 6 1,4-Dioxane 40 65:23:12 7 2-Me-THF 40 78:17:5 8 CHCl3 40 70:16:14 9 CH2Cl2 reflux 81:10:9  3 Scheme 3. Substrate scope.a,b  aReaction conditions: 1 (0.423 mmol; 0.036 g), 2 (0.423 mmol), H2O2 30% (0.465 mmol; 0.047 mL), CH3CN (0.32 mL), 40°C, 24 h. bIsolated yield.  cDetermined by crude 1H NMR.     Finally, three representatives aliphatic phosphonium ylides such as 2p-r could also be accommodated providing the corresponding derivative 5p-r in good to high yields (68-95%). On the other hand, when ethyl 2-(triphenylphosphoranylidene) acetate, was employed, intermediate 4s instead of γ-lactone 5s was recovered from the reaction mixture (36% yield), most likely because of its less reactivity toward intramolecular oxa-conjugate cyclization.[48]  Conclusion    In conclusion, the results reported in this paper provide a new synthetic application of α‐hydroxy cyclobutanone for the construction of important γ-lactones with moderate to good yields through a tandem sequence combining Baeyer-Villiger reaction and Wittig/oxa-Michael addition.  Data availability  Data will be made available on request.  Declaration of Competing Interest  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.  Acknowledgments Financial support from the MUR (Ministero Università e Ricerca) and by the University of Cagliari (FIR 2019). C.I.N.M.P.I.S. “Consorzio Interuniversitario Nazionale di Ricerca in Metodologie e Processi Innovativi di Sintesi” is acknowledged. We acknowledge the CeSAR (Centro Servizi Ricerca d'Ateneo) core facility of the University of Cagliari and Dr. Sandrina Lampis for assistance with the generation of NMR data. Appendix A. Supplementary data  References   1 J. Hur, J. Jang, J. Sim, Int. J. Mol. Sci. 2021, 22, 2769–2816  2 R. Zhu, S. L. Buchwald, J. Am. Chem. Soc. 2015, 137, 8069–8077.  3 W. Sha, S. Ni, J. Han, Y. Pan, Org. Lett. 2017, 19, 5900–5903. 4 F. Wu, S. Stewart, J. P. Ariyarathna, W. Li, ACS Catal. 2018, 8, 1921–1925. 5 Y. Da, S. Han, X. Du, S. Liu, L. Liu, J. Li, Org. Lett. 2018, 20, 5149–5152.  6 B. Du, Y. Wang, H. Mei, J. Han, Y. Pan, Adv. Synth. Catal. 2017, 359, 1684–1690. 7 J. Zhang, K. Zhou, J. Wu, Org. Chem. Front. 2018, 5, 813–816. 8 Y. Wang, L. Deng, J. Zhou, X. Wang, H. Mei, J. Han, Y. Pan, Adv. Synth. Catal. 2018, 360, 1060–1065.    9 Y. Qiu, W.-J. Kong, J. Struwe, N. 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Tandem Baeyer–Villiger/Wittig/oxa-Michael addition: One-step to 5-substituted γ-lactones

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Tandem Baeyer–Villiger/Wittig/oxa-Michael addition: One-step to 5-substituted γ-lactones

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