Tag Archives: Heterocycles

Regio- and Enantioselective Aminofluorination of Alkenes

Wangqing Kong, Pascal Feige, Teresa de Haro, and Cristina Nevado
Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201208471

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Multisubstituded, saturated 5-, 6- and 7- membered heterocycles are part of many bio-active molecules. Fluorinated derivatives of such structures have also been shown to display better pharmacological properties such as solubility and metabolic stability. Hence their enantioselective preparation in a facile and efficient manner is of great interest for synthetic chemists.

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Classical approaches involve cycloadditions such as inverse-electron demand Diels-Alder or [2,3] azomethine ylide reactions1, whereas more modern approaches focus on transition metal catalysed aminoalkylations2. Cristina Nevado’s group in Zurich, have recently reported a metal-free regio- and enantioselective aminofluorination for the preparation of 6- and 7-membered fluorinated heterocyclic compounds.

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The reaction is highly regioselective yielding the 6-endo-cyclisation product only. Using their newly discovered conditions they investigated the scope of the intramolecular aminofluorination.

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From the data presented in the supporting information, aromatic substituents seem to have a positive influence on enantioselective induction. The preparation of 7-membered rings was also performed. However it required the addition of a catalytic amount of [(Ph3P)AuNTf2].

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The authors also investigated the scope of intermolecular aminofluorinations in a non-asymmetric manner, using p-xyleneIF2 as the fluorine source.

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This method provides a facile route to fluorinated surrogates of saturated heterocyclic compounds. It would be interesting to see it applied for the preparation of morpholine or piperazine containing compounds in the future.

References:

1. a) Geraldine Masson et al. Org. Bio. Chem. 2012 ; b) Marco Potowski et al. Angew. Chem. Int. Ed. 2012.

2. a) Josephine S. Nakhla et al. Org. Let. 2007 ; b) Matthew L. Leathen et al. J. Org. Chem. 2009.

Solar-Driven Incorporation of Carbon Dioxide into α-Amino Ketones

Naoki Ishida, Yasuhiro Shimamoto, and Masahiro Murakami
Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201206166

Preparation of cyclic carbonates by incorporation of CO2 into strained cyclic systems is well known and widely exploited. A standard synthesis of these compounds is through addition of epoxide into CO2 followed by ring expansion. Murakami and co-workers take a similar approach in cyclic carbonate synthesis in order to demonstrate a process involving 2 goals in green chemistry: CO2 incorporation, and sunlight activation.

The authors show that azetidine derivatives can be prepared from α-methylaminoketones through irradiation with sunlight alone. These high energy intermediates are relatively stable and their stored solar energy can be released in reaction with CO2 under mild conditions. The reaction can tolerate various aryl groups, but chain length is fixed as a hydroxypyrrolidine derivative is too stable to undergo ring opening.

Substitution of Two Fluorine Atoms in a Trifluoromethyl Group: Regioselective Synthesis of 3-Fluoropyrazoles

Kohei Fuchibe, Masaki Takahashi, and Junji Ichikawa
Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201206946

We don’t often consider the trifluoromethyl group as a reactive centre. But it is, of course, a highly polarised moiety and, under the right conditions, fluoride can act as a competent leaving group. Ichikawa and coworkers employ hydrazines as nucleophiles in two successive displacements of fluoride from vinyl trifluoromethyl adducts to give 3-fluoropyrazole scaffolds.

After testing other possible reaction pathways, they postulate that the reactive intermediate in the cyclisation step, after loss of the tosyl anion, is an azomethine ylide.

Facile Preparation of Indoles and 1,2-Benzothiazine 1,1-Dioxides

Masahito Yamagishi, Ken Nishigai, Azusa Ishii, Takeshi Hata and Hirokazu Urabe Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201201024

The addition of nucleophiles into electron deficient π-systems is a powerful and widely used concept in synthesis. Urabe and co-workers have shown that bromoalkynes can behave as competent electrophiles for such additions and demonstrate how the unique products of sulfonamide addition can act as precursors for heterocycle synthesis.

Addition under basic conditions with heating results in isolation of the cis-enamine as the only observed product. With an aryl substituent on the nitrogen, the adduct undergoes cyclisation by palladium catalysis to give the indole product. This process can be applied in a one-pot procedure, giving the indole scaffold in one step.

When an arylsulfonamide nucleophile does not contain an N-aryl substituent, an alternative heterocyclic system can be isolated from subjecting the addition product to palladium catalysis. 1,1-dioxobenzothiazines can be prepared using a 10 mol% loading of palladium acetate.

The higher catalyst loading is required for the less favourable cyclisation. When an N-aryl arylsulfonamide is subjected to cyclisation conditions only the indole product is observed.