The synthetic versatility of fluoroiodomethane: recent applications as monofluoromethylation platform.

In recent years, fluoroiodomethane (CH2FI) has emerged as an easy-to-handle, non-ozone depleting agent and readily available platform for monofluoromethylation strategies. Recent applications in nucleophilic substitutions, lithiation reactions, transition-metal catalyzed transformations, radical processes, and 18F-radiolabelling chemistry showcase the potential of this reagent for the preparation of organofluorine compounds. In this minireview, we provide an update to the field covering the recent relevant literature on the use of CH2FI.

Dynamic Phenomena and Complexation Effects in the α-Lithiation and Asymmetric Functionalization of Azetidines.

In this work it is demonstrated that enantiomerically enriched N-alkyl 2-oxazolinylazetidines undergo exclusive α-lithiation, and that the resulting lithiated intermediate is chemically stable but configurationally labile under the given experimental conditions that afford enantioenriched N-alkyl-2,2-disubstituted azetidines. Although this study reveals the configurational instability of the diastereomeric lithiated azetidines, it points out an interesting stereoconvergence of such lithiated intermediates towards the thermodynamically stable species, making the overall process highly stereoselective (er > 95:5, dr > 85:15) after trapping with electrophiles. This peculiar behavior has been rationalized by considering the dynamics at the azetidine nitrogen atom, the inversion at the C-Li center supported by in situ FT-IR experiments, and DFT calculations that suggested the presence of η3-coordinated species for diastereomeric lithiated azetidines. The described situation contrasted with the demonstrated stability of the smaller lithiated aziridine analogue. The capability of oxazolinylazetidines to undergo different reaction patterns with organolithium bases supports the model termed "dynamic control of reactivity" of relevance in organolithium chemistry. It has been demonstrated that only 2,2-substituted oxazolinylazetidines with suitable stereochemical requirements could undergo C=N addition of organolithiums in non-coordinating solvents, leading to useful precursors of chiral (er > 95:5) ketoazetidines.

Development of a Continuous Flow Synthesis of 2-Substituted Azetines and 3-Substituted Azetidines by Using a Common Synthetic Precursor.

The generation and functionalization, under continuous flow conditions, of two different lithiated four-membered aza-heterocycles is reported. N-Boc-3-iodoazetidine acts as a common synthetic platform for the genesis of C3-lithiated azetidine and C2-lithiated azetine depending on the lithiation agent. Flow technology enables easy handling of such lithiated intermediates at much higher temperatures compared to batch processing. Flow technology combined with cyclopentylmethyl ether as an environmentally responsible solvent allows us to address sustainability concerns.

Flow Technology for Telescoped Generation, Lithiation and Electrophilic (C3 ) Functionalization of Highly Strained 1-Azabicyclo[1.1.0]butanes.

Strained compounds are privileged moieties in modern synthesis. In this context, 1-azabicyclo[1.1.0]butanes are appealing structural motifs that can be employed as click reagents or precursors to azetidines. We herein report the first telescoped continuous flow protocol for the generation, lithiation, and electrophilic trapping of 1-azabicyclo[1.1.0]butanes. The flow method allows for exquisite control of the reaction parameters, and the process operates at higher temperatures and safer conditions with respect to batch mode. The efficiency of this intramolecular cyclization/C3-lithiation/electrophilic quenching flow sequence is documented with more than 20 examples.

Flow technology enabled preparation of C3-heterosubstituted 1-azabicyclo[1.1.0]butanes and azetidines: accessing unexplored chemical space in strained heterocyclic chemistry.

The use of flow technology as an enabling tool for accessing 1-azabicyclo[1.1.0]butanes bearing strained 3-, 4-, and 5-membered O-heterocycles with C3(N-het)-C2(O-het) connectivity is reported. Reactivity and chemoselectivity (N-ring vs. O-ring) were also evaluated. New chemical space has been explored and new structural motifs such as ABB-aziridines or spiro azetidine-oxazetidines are also reported.

Flow Microreactor Technology for Taming Highly Reactive Chloroiodomethyllithium Carbenoid: Direct and Chemoselective Synthesis of α-Chloroaldehydes.

A straightforward flow synthesis of α-chloro aldehydes has been developed. The strategy involves, for the first time, the thermal unstable chloroiodomethyllithium carbenoid and carbonyl compounds. A batch versus flow comparative study showcases the superb capability of flow technology in prolonging the lifetime of the lithiated carbenoid, even at -20 °C. Remarkably, the high chemoselectivity realized in flow allowed for preparing polyfunctionalized α-chloro aldehydes not easily accessible with traditional batch procedures.

Stereo- and Enantioselective Addition of Organolithiums to 2-Oxazolinylazetidines as a Synthetic Route to 2-Acylazetidines.

A new synthetic route to N-alkyl-2-acylazetidines was developed through a highly stereoselective addition of organolithiums to N-alkyl-2-oxazolinylazetidines followed by acidic hydrolysis of the resulting oxazolidine intermediates. This study revealed an unusual reactivity of the C=N bond of the oxazoline group when reacted with organolithiums in a non-polar solvent such as toluene. The observed reactivity has been explained considering the role of the nitrogen lone pair of the azetidine ring as well as of the oxazolinyl group in promoting a complexation of the organolithium, thus ending up with the addition to the C=N double bond. The high level of stereoselectivity in this addition is supported by DFT calculations and NMR investigations, and a model is proposed for the formation of the oxazolidine intermediates, that have been isolated and fully characterized. Upon acidic conditions, the oxazolidine moieties were readily converted into 2-acylazetidines. This synthetic approach has been applied for the preparation of highly enantioenriched 2-acylazetidines starting from chiral not racemic N-alkyl-2-oxazolinylazetidines.

1,3-Dibromo-1,1-difluoro-2-propanone as a Useful Synthon for a Chemoselective Preparation of 4-Bromodifluoromethyl Thiazoles.

We report herein a synthetic protocol for the preparation of 1,3-dibromo-1,1-difluoro-2-propanone, a new synthon used for the first time in a reaction with aromatic amines and sodium thiocyanate, leading to thiazoles which are useful candidates in drug discovery programs. The new synthon allows to introduce a bromodifluoromethyl group at the C4 of the thiazole, and it is amenable of further transformation such as the Br/F exchange useful in radiopharmaceutics. Application of the strategy to the preparation of a precursor of the biologically relevant DF2755Y is also reported.