Regioselective functionalization of 2-arylazetidines: evaluating the ortho-directing ability of the azetidinyl ring and the α-directing ability of the N-substituent

Degennaro, Leonardo; Zenzola, Marina; Trinchera, Piera; Carroccia, Laura; Giovine, Arianna; Romanazzi, Giuseppe; Falcicchio, Aurelia; Luisi, Renzo

doi:10.1039/c3cc48555b

Cited by 40 publications

(17 citation statements)

References 29 publications

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“…First, we investigated the reactivity of 1‐methyl‐2‐phenylazetidine ( 1 a ), chosen as a reference substrate, towards bases other than n ‐hexyllithium ( n HexLi). We found that n HexLi was effective in the regioselective ortho ‐lithiation of 1 a under very mild conditions 9a. Nevertheless, as reported in Table 1, other organolithium reagents and lithium amides were taken into consideration for two main reasons: 1) to explore the possibility to switch the regioselectivity (i.e.…”

Section: Resultssupporting

confidence: 58%

Harnessing the ortho‐Directing Ability of the Azetidine Ring for the Regioselective and Exhaustive Functionalization of Arenes

Zenzola

Degennaro

Trinchera

et al. 2014

Chemistry A European J

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This work demonstrates how the directing ability of the azetidine ring could be useful for regioselective ortho-C-H functionalization of aryl compounds. Robust polar organometallic (lithiated) intermediates are involved in this synthetic strategy. The reagent n-hexyllithium emerged as a safer, yet still effective, basic reagent for the hydrogen/lithium permutation relative to the widely used reagent nBuLi. Two different reaction protocols were discovered for regioselective lithiation at the ortho positions adjacent to the azetidine ring, which served as a toolbox when other competing directing groups were installed on the aromatic ring. The coordinating ability of the azetidine nitrogen atom, as well as the involvement of dynamic phenomena related to the preferential conformations of 2-arylazetidine derivatives, were recognized to be responsible for the observed reactivity and regioselectivity. A site-selective functionalization of the aromatic ring was achieved for aryl azetidines with either coordinatively competent groups (e.g. methoxy) or inductively electron-withdrawing substituents (e.g. chlorine and fluorine). By fine-tuning the reaction conditions, regioselective introduction of several substituents on the aromatic ring could be realized. Several substitution patterns were accomplished, which included 1,2,3-trisubstitution, 1,2,3,4-tetrasubstitution, and 1,2,3,4,5-pentasubstitution, up to the exhaustive substitution of the aromatic ring.

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Section: Resultssupporting

confidence: 58%

Harnessing the ortho‐Directing Ability of the Azetidine Ring for the Regioselective and Exhaustive Functionalization of Arenes

Zenzola

Degennaro

Trinchera

et al. 2014

Chemistry A European J

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“…However, just few examples on this topic have been reported mainly by Seebach on azetidines with an electron-withdrawing group (EWG) as the Nsubstituent such as N-nitrosoazetidine and N-(triphenylacetyl)azetidine (Scheme 26). [66] N-Methyl-2-arylazetidines were smoothly ortho-lithiated upon treatment at 20°C with n-HexLi in the presence of TMEDA (Scheme 28). [64] complished, leading to azetidines 108a,b although in low yield, only by using in situ-quenching conditions and performing the deprotonation reaction of 107 with n-hexyllithium (n-HexLi) in 2-MeTHF at -84°C (Scheme 27).…”

Section: Lithiated Arylazetidinesmentioning

confidence: 99%

Complexation Phenomena and Dynamics at Work in the Lithiation Reactions of Small‐Ring Heterocycles: Regio‐ and Stereoselectivity

2014

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This Microreview focuses on the regio- and stereoselective lithiation of small-ring heterocycles such as aryl-substituted oxiranes, aziridines, azetidines, oxetanes, and tetrahydrofurans highlighting some useful selected synthetic applications extracted from recent literature. It will be shown, in particular, that regio- and stereoselectivity and the configurational stability of the above lithiated species are controlled by a subtle interplay of factors. Aggregation, complexation phenomena, dynamics at the heteroatom of the heterocyclic ring, substitution in both the aryl and the heterocyclic ring, solvent polarity, temperature, and ligands play a crucial role. The ability of the afore-mentioned heterocycles as important directed metalation groups for the arene ortho-functionalization is also discussed as well as the carbene-like nature exhibited by some lithiated epoxides and aziridines. This Microreview focuses on the regio- and stereoselective preparation of α- and ortho-lithiated oxiranes, aziridines, oxetanes, azetidines, and tetrahydrofurans with special emphasis on factors such as carbene-like character, aggregation, complexation phenomena and dynamics which strongly influence their applications to synthetic chemistry. Recent selected examples extracted from the literature are critically analysed and commented

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“…[7][8][9][10] A common limitation of these approaches is that they often require functional-group installation prior to azetidine formation. [11,12] We wondered whether simple access to azetidine nitrones could provide an opportunity for the development of simple functionalization strategies to access highly substituted examples of these strained ring systems from ac ommon unsaturated intermediate.…”

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confidence: 99%

Facile Synthesis of Azetidine Nitrones and Diastereoselective Conversion into Densely Substituted Azetidines

et al. 2017

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An electrocyclization route to azetidine nitrones from N-alkenylnitrones was discovered that provides facile access to these unsaturated strained heterocycles.R eactivity studies showed that these compounds undergo av ariety of reduction, cycloaddition, and nucleophilic addition reactions to form highly substituted azetidines with excellent diastereoselectivity.T aken together,t hese transformations provide af undamentally different approacht oa zetidines ynthesis than traditional cyclization by nucleophilic displacement and providen ovel access to av ariety of underexplored strained heterocyclic compounds. Scheme 2. Cycloaddition and reduction of azetidine nitrones. THF = tetrahydrofuran, Tf = trifluoromethanesulfonyl.

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Regioselective functionalization of 2-arylazetidines: evaluating the ortho-directing ability of the azetidinyl ring and the α-directing ability of the N-substituent

Cited by 40 publications

References 29 publications

Harnessing the ortho‐Directing Ability of the Azetidine Ring for the Regioselective and Exhaustive Functionalization of Arenes

Harnessing the ortho‐Directing Ability of the Azetidine Ring for the Regioselective and Exhaustive Functionalization of Arenes

Complexation Phenomena and Dynamics at Work in the Lithiation Reactions of Small‐Ring Heterocycles: Regio‐ and Stereoselectivity

Facile Synthesis of Azetidine Nitrones and Diastereoselective Conversion into Densely Substituted Azetidines

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