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Normal, Abnormal, and Cascade Wittig Olefinations of -Oxoketenes

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Normal, Abnormal, and Cascade Wittig Olefinations of -Oxoketenes Normal, Abnormal, and Cascade Wittig Olefinations of α-Oxoketenes David Pierrot, Marc Presset, Jean Rodriguez, Damien Bonne, Yoann Coquerel To cite this version: David Pierrot, Marc Presset, Jean Rodriguez, Damien Bonne, Yoann Coquerel. Normal, Abnormal, and Cascade Wittig Olefinations of α-Oxoketenes. Chemistry - A European Journal, Wiley-VCH Verlag, 2018, 24 (43), pp.11110-11118. 10.1002/chem.201801533. hal-01980647 HAL Id: hal-01980647 https://hal.archives-ouvertes.fr/hal-01980647 Submitted on 14 Jan 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. DOI:10.1002/chem.201801533 Full Paper & Synthetic Methods |Hot Paper| Normal, Abnormal, and Cascade Wittig Olefinations of a-Oxoketenes David Pierrot,[a] Marc Presset,[a, b] Jean Rodriguez,[a] Damien Bonne,*[a] andYoann Coquerel*[a] Abstract: a-Oxoketenes generated in situ by athermal Wolff functionofthe substrates combination employed. Mechanis- rearrangement have been found to participate as 1,2- and tic experimental and computational studies provided afull 1,4-ambident C-electrophilic/O-nucleophilicreagents to- rational for these reactivity switches. Some unusualmecha- wards donor/acceptor carbonyl-stabilized Wittig ylides. This nistic features for Lewis acid-free Wittig olefinations were resulted in the very direct and practical syntheses of func- identified in this series such as the involvement of betaine tionalized allenes by anormalWittig olefination, 4H-pyran-4- intermediates and some degree of reversibility in the normal ones by an abnormal Wittig olefination, or 4H-pyranylidenes Wittig olefination. The abnormal Wittig olefination was fully following aWittig/abnormal Wittig cascadesequence as a uncovered. Introduction ketenes. Several examples of the anticipated a,a’-bisoxoallene synthesis could indeedberealized.However, in anumber of a-Oxoketenes are denselyfunctionalized, highly reactive, elec- cases the reaction between a-oxoketenes and carbonyl-stabi- trophilicreaction intermediates of past and current great inter- lized ylides followed alternative pathways involving either ab- est, not only because of mechanistic and theoretical considera- normalWittig olefinations or cascade normal/abnormalWittig tions, but also because of their rich chemistry as building processes to afford 4H-pyran derivatives. In this article, we blocks in organic synthesis.[1] With very few exceptions, they report in full detail the results of our experimental and theoret- cannotbeisolated under ordinary conditions andmust be ical investigations on the synthetically valuable chemical di- generated in situ. Thetwo most convenient and commonly chotomyinthe reactions of a-oxoketenes with carbonyl-stabi- employed methods for the generation of a-oxoketenes are the lized Wittig ylides. thermaldecomposition of dioxinones,[2] and the thermalor photochemical Wolff rearrangementof2-diazo-1,3-dicarbonyl [3] compounds. For the work described herein, and based on Results and Discussion some precedents with simple ketenes,[4] it was considered that unsymmetrically functionalized a,a’-bisoxoallenes, for example, Our investigations started with the acyclicdiazo compounds 4a–f,aclass of chiral molecules difficult to obtain and only 1a–c,which were allowed to reactwith the representative availablethrough relatively complex multistep synthetic se- Wittig ylides 2a–c in toluene at 140 or 1708Cunder microwave quences,[5] could be readily preparedbyaWolffrearrange- irradiation conditions promoting rapid, quantitative, and regio- ment/Wittig olefination cascade reaction from diazo com- selective(when applicable), Wolffrearrangements of the diazo pounds and carbonyl-stabilized ylides via intermediate a-oxo- compounds 1 into the corresponding a-oxoketenes 3 (Scheme 1).[1e–h] As expected, the desired a,a’-bisoxoallenes 4a–f were obtained in fair to good yields, unlocking the practi- [a] Dr.D.Pierrot,Dr. M. Presset,Prof. Dr.J.Rodriguez, Dr.D.Bonne, cal synthesis of this valuable class of compounds. As an inter- Dr.Y.Coquerel Aix MarseilleUniv,CNRS, Centrale Marseille, iSm2 esting observation, we also found evidence for the formation Marseille(France) of aminor amount of g-pyrone 5l (15%)inthe reaction be- E-mail:[email protected] tween diazo 1a and ylide 2a.The formationof 5l can be ra- [email protected] tionalized by invoking a1,4-C-electrophilic/O-nucleophilicbe- [b] Dr.M.Presset havior of the a-oxoketene 3a triggering an abnormal Wittig Presentaddress:Universitÿ Paris Est, ICMPE(UMR 7182), CNRS, UPEC [6] 2-8 rue HenriDunant, 94320 Thiais (France) olefination (see mechanisticdiscussion below). g-Pyrones are Supporting information and the ORCID identification number(s) for the au- valuablechemical moieties with arelatively frequent occur- thor(s) of this article can be found under: rence in biologically activenatural and non-naturalproducts.[7] https://doi.org/10.1002/chem.201801533.Itcontains the compound num- Existingsynthetic methods forging g-pyrones are often of lim- bering employed,general experimental considerations, some complementa- ited breadth, hampering the explorationoftheir potential in ry experimentalobservations, the detailedexperimentalprocedures, the [7,8] characterization data and copies of NMR spectrafor all compounds, and chemistry and chemical biology, andalternative methods the full-details computational mechanistic study. are desirable. Chem. Eur.J. 2018, 24,11110 –11118 11110 ⌫ 2018 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Full Paper intermediate derived from 2-diazo-1,3-cyclohexanone (1d;R1, 2 R =-(CH2)3-) reacted with the methyl ketone-stabilized Wittig ylide 2d (R3 = Me) to afford the fused bicyclic 4H-pyran-4-one 5a in 69%yield, the structure of which was confirmedbyX- ray diffraction analysis. Similarly,4H-pyran-4-ones incorporating either an alkyl (in 5b), hindered alkyl (in 5c, 5d and 5i), phenyl (in 5e), carbethoxyl (in 5f), or carbethoxymethyl (in 5g)sub- stituent, or asimple hydrogen atom (in 5h)atthe 6position, could be prepared. The reactionwith the non-symmetric diazo 1 2 ketoamide 1c (R =NMe2,R=Me) afforded exclusively the 2- dimethylamino-functionalized 4H-pyran-4-one 5j in 74 %yield, following aregioselective Wolffrearrangement of the diazo compound. Avariation of the reactionwas used for the prepa- ration of the 4H-pyran-4-one 5k having the 3positionunsub- stituted(R2 =H), which involved the thermolytic decomposi- tion of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (1h)for the genera- tion of the required monosubstituted a-oxoketene intermedi- ate.[2] In acontrol experiment, the irradiation with microwaves of atoluene solutionofthe diazo compound 1e (R1,R2 = -CH2C(CH3)2CH2-) andthe phosphorous ylide 2d for 15 minutes at 80 or 1308C(which are temperatures that do not or only Scheme1. Synthesis of a,a’-bisoxoallenes 4 by normal Wittig olefination of a-oxoketenes 3. slowly promote the Wolff rearrangement of 1e)left the start- ing materials essentially unchanged, showing that the ylide is inert toward the diazo compound atthese temperatures. Over- Stimulated and intriguedbythese early results,aseries of all, asimple and rapid synthetic method to prepare diversely representative in situ generated a-oxoketenes were allowed to substituted and functionalized 4H-pyran-4-ones has been dis- react with aselection of carbonyl-stabilized Wittig ylides. It covered, revealing that the abnormal Wittig olefination is not was actually found that a-oxoketenes generally react with just alaboratory oddity[6] but ageneral reaction. It nicely com- ketone-stabilized, and to some extent aldehyde-stabilized, plementsexisting methods to synthesize g-pyrones.[7,8] Nota- ylides 2 via abnormal Wittig olefinations rather than regular bly,ynol ethers have in the past been reported to undergo in- Wittig olefinations, whichresulted in the synthesisofpolysub- verse-demand Diels–Alder cycloaddition with a-oxoketenes to stitutedand functionalizedmonocyclic and fused bicyclic g-py- regioselectively afford g-pyronesoftype 5 havinganalkoxide rones 5a–k in fair to good yields (Scheme2). The a-oxoketene R3 substituent.[8c,d] As to the complementary method reported herein, the Wittig ylides 2a,d–h may be regarded as synthetic equivalents of terminal alkynes capable of undergoing regiose- lective [4+2] cycloaddition reactions with a-oxoketenes (Scheme 3). Scheme3. Carbonyl-stabilizedWittig ylides as synthetic equivalents of al- kynes. In sharp contrast to the above results, the combination of the a-oxoketene derived from the diazo 1e and the ester-sta- bilizedWittig ylide 2c did not produce the a,a’-bisoxoallene 4g or the g-pyrone 5m,but the 4H-pyranylidene 6a in 43% yield together with asignificant proportion of the a-oxoketene dimer [Scheme 4, Eq. (a)].Because two molecules of ylides were clearly incorporatedinthe product 6a,the same reaction was attempted with two equivalents of the ylide, which afford- Scheme2. Synthesis of g-pyrones 5 by abnormal Wittig olefination of a-oxo- ed this time the 4H-pyranylidene 6a in 89%yield. This pseudo ketenes 3.[a] The reaction also afforded the products 6f(22%) and iso-6
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