Microwave‐Assisted 1,3‐Dipolar Cycloaddition: an Eco‐Friendly Approach to Five‐Membered Heterocycles

Piñeiro, Marta; Melo, Teresa M. V. D. Pinho e

doi:10.1002/ejoc.200900644

Cited by 85 publications

(19 citation statements)

References 132 publications

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“…However the overall time for the completion of the synthesis of 5-(β-dimethylaminoethyl)-tetrazole (IV) is long, 18 h. To reduce the reaction time we intensifi ed the process by microwave irradiation. Note that the microwave activation is more and more used in the processes of 1,3-dipolar cycloaddition, in particular, in those resulting in the formation of NH-unsubstituted 5-R-tetrazoles [3,[15][16][17]. In this study we observed a signifi cant promotion effect: The application of the microwave irradiation additionally to the common convection heating 5-fold reduced the reaction time (to 3 h).…”

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confidence: 61%

Vinyltetrazoles: I. Synthesis of NH-unsubstituted 5-vinyltetrazole

et al. 2010

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The NH-unsubstituted 5-vinyltetrazole was obtained in 55% yield by exhaustive methylation of 5-(β-dimethylaminoethyl)tetrazole with dimethyl sulfate at the terminal dimethylamino group with the subsequent elimination of a proton from the α-CH 2 group and Hofmann β-cleavage of the intermediate 5-(β-trimethylammoniumethyl)tetrazolide methyl sulfate. The microwave irradiation was shown to reduce 5-fold the time of the synthesis of the initial substrate, 5-(β-dimethylaminoethyl)tetrazole.NH-Unsubstituted 5-vinyltetrazole (I) and its alkyl derivatives, e.g., II and III, have a considerable practical interest as substrates for preparation of polymers with a high nitrogen content, poly(vinyl-5-yltetrazoles) [1]. These polymers and materials based thereon are required by to-day medicine and engineering [2]. The poly(vinyl-5-yltetrazoles) can underlie the fi lter materials for the purifi cation of the biological fl uids from heavy metal ions and radionuclides [3], superabsorbents of moisture [4], effi cient energy-rich materials [5].Up till now only few chemical reactions of NHunsubstituted 5-vinyltetrazole (I) are known at the endocyclic nitrogen atoms. Arnold and Thatcher showed that the acylation of 5-vinyltetrazole (I) with acetic anhydride followed by the thermolysis of the intermediate N-acyl derivative occurring with elimination of a nitrogen molecule led to the formation of 2-methyl-5-vinyl-1,3,4-oxadiazole [6]. The reaction of 5-vinyltetrazoles I-III with PdCl 2 resulted in the formation of coordination compounds of the general formula PdL 2 Cl 2 [7]. On replacing in these processes palladium chloride with CuCl 2 or NiCl 2 the arising coordination compounds do not contain chlorine in their composition. Therefore Kizhnyaev and Kruglova [7] suggest that here the ligand is the corresponding anionic form 5-vinyltetrazolide. In [8] the rate constants were measured of tetrazole I alkylation with methyl iodide in acetonitrile in the presence of triethylamine, and the ratio was established of isomeric reaction products, 1-(II) and 2-methyl-5-vinyltetrazoles (III). The reactions involving the vinyl group of tetrazole I save the polymerization processes [1] are virtually unknown notwithstanding the obvious possibility to obtain in this way new promising compounds. The development of research in this fi eld of the tetrazole chemistry is hampered by the limited availability of the initial compound, NH-unsubstituted 5-vinyltetrazole (I). Evidently the development of an effi cient procedure of the synthesis of NH-unsubstituted 5-vinyltetrazole (I) is an urgent task.The most wide-spread preparation method for NHunsubstituted 5-R-tetrazoles is the 1,3-dipolar cycloaddition of azides to nitriles. Recently versatile versions of this process were developed permitting the preparation of various 5-R-tetrazoles (R = Alk, Ar, Ht) in good yield and under relatively mild conditions [3]. However the only example of the synthesis of NH-unsubstituted 5-vinyltetrazole (I) directly from acrylonitrile was reported

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confidence: 61%

Vinyltetrazoles: I. Synthesis of NH-unsubstituted 5-vinyltetrazole

et al. 2010

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“…To remove the Boc and tert ‐butyl protecting groups, compounds 7 and 8 were treated with trifluoroacetic acid in CH 2 Cl 2 at RT, and after completion of the reactions amino acids 9 and 10 , respectively, were precipitated from water at pH 6–7 in excellent yields. With the cyclization precursors 9 and 10 now in hand, we performed the first decarboxylative cycloaddition by heating 9 with one equivalent of 6‐chlorisatin ( 11 ) in methanol at 100 °C for 30 min in a microwave reactor . We were able to isolate an inseparable mixture of the diastereomers rac ‐ 12 a and rac ‐ 12 b in 23 % yield and a diastereomeric ratio of 1:3.…”

Section: Methodsmentioning

confidence: 99%

Targeted Synthesis of Complex Spiro[3H‐indole‐3,2′‐pyrrolidin]‐2(1H)‐ones by Intramolecular Cyclization of Azomethine Ylides: Highly Potent MDM2–p53 Inhibitors

et al. 2018

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Mouse double minute 2 (MDM2) is a main and direct inhibitor of the crucial tumor suppressor p53. Reports from initial clinical trials showed that blocking this interaction with a small‐molecule inhibitor can have great value in the treatment of cancer for patients with p53 wild‐type tumors; however, it also revealed dose‐limiting hematological toxicities and drug‐induced resistance as main issues. To overcome the former, an inhibitor with superior potency and pharmacokinetic properties to ultimately achieve full efficacy with less‐frequent dosing schedules is required. Toward this aim, we optimized our recently reported spiro‐oxindole inhibitors by focusing on the crucial interaction with the amino acid side chain of His96 MDM2 . The designed molecules required the targeted synthesis of structurally complex spiro[indole‐3,2′‐pyrrolo[2,3‐ c ]pyrrole]‐2,4′‐diones for which we developed an unprecedented intramolecular azomethine ylide cycloaddition and investigated the results by computational methods. One of the new compounds showed superior cellular potency over previously reported BI‐0252. This finding is a significant step toward an inhibitor suitable to potentially mitigate hematological on‐target adverse effects.

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“…Other factors affecting the efficiency of the reaction between hydrazones and alkenes are microwave irradiation 159 and catalysts. 160 ± 167 The [3+2]-cycloaddition of azomethine imine 126a, formed in situ from hydrazone 127a, to the cyclopentadiene proceeds under mild conditions and at a higher rate when Lewis acids [BF 3 .…”

Section: Scheme 49mentioning

confidence: 99%