Laijun Zhang

Silver-mediated trifluoromethylation-iodination of arynes.

An unprecedented silver-mediated vicinal trifluoromethylation-iodination of arynes that quickly introduces CF(3) and I groups onto aromatic rings in a single step to give o-trifluoromethyl iodoarenes has been developed. A new reactivity of AgCF(3) has been revealed, and 2,2,6,6-tetramethylpiperidine plays an important role in this difunctionalization reaction.An unprecedented silver-mediated vicinal trifluoromethylation-iodination of arynes that quickly introduces CF3 and I groups onto aromatic rings in a single step to give o-trifluoromethyl iodoarenes has been developed. A new reactivity of AgCF3 has been re

Nucleophilic Fluoroalkylation of α,β-Enones, Arynes, and Activated Alkynes with Fluorinated Sulfones : Probing the Hard/Soft Nature of Fluorinated Carbanions

We have successfully accomplished the nucleophilic fluoroalkylation of alpha,beta-enones, arynes, and activated alkynes with fluorinated sulfones. It was found that for acylic alpha,beta-enones, although the reaction medium and the structure of the enones can all influence the regioselectivity of the nucleophilic alkylation reactions, the hard/soft nature of the carbanions played a major role. By using the 1,4- and 1,2-addition product ratio as a probe to determine the hard/soft nature of the above-mentioned four halogenated carbanions, the order of the softness of these carbanions can be given as follows: [(PhSO2)2CF(-)] (20) approximately = PhSO2CCl2(-) (32) > PhSO2CHF(-) (31) > PhSO2CF2(-) (30). In the case of fluoroalkylation of aryne (35 as the precursor) and alpha,beta-acetylenic ketones 46 with fluorobis(phenylsulfonyl)methane (21), fluorobis(phenylsulfonyl)methylated arenes 36 and beta-fluorobis(phenylsulfonyl)methylated alpha,beta-enones 47 were obtained as the corresponding products in good yields. During the reaction between 2-fluoro-2-(phenylsulfonyl)acetophenone (34) and arynes or activated alkynes 46, an intramolecular tandem reaction process leads to the formation of acyl-fluoroalkylated arenes 43 or alpha-acyl-beta-fluoroalkylated alpha,beta-enones 48. It turned out that the softness of a fluorine-bearing carbanion (such as 20 or 33 derived from 21 or 34) plays a crucial role for the success of the nucleophilic fluoroalkylation reactions with arynes and some activated alkynes (alpha,beta-acetylenic ketones).

Copper-Mediated Fluoroalkylation Reactions with Iododifluoroacetamides: Controlling the Selectivity among Cross-Coupling, Intramolecular Cyclization, and Homocoupling Reactions

Cu-mediated fluoroalkylation reactions with iododifluoroacetamides 1 have been systematically investigated. It was found that three types of reactions may coexist in Cu-mediated reactions between iododifluoroacetamides and aryl/alkenyl iodides: cross-coupling, intramolecular cyclization, and homocoupling reactions. The selectivity among these three types of reactions could be controlled by tuning the substituents on the nitrogen atom of iododifluoroacetamides, and/or by removing the cross-coupling reaction partner (aryl/alkenyl halides). The general rule is as follows: (a) in the presence of proper aryl/alkenyl iodides, the cross-coupling products 2 (or 6) are generally formed as the major products; (b) in the absence of aryl/alkenyl iodides, and when R(1) = alkyl and R(2) = aryl groups, or when R(1) = R(2) = aryl groups, the intramolecular cyclization products 3 can be formed predominantly; and (c) in the absence of aryl/alkenyl iodides, and when R(1) = R(2) = alkyl groups, or when R(1) = H and R(2) = alkyl, aryl groups, the homocoupling products 4 can be formed dominantly. Our experimental results also indicate that in many cases when cross-coupling, homocoupling, and intramolecular cyclization reactions coexist in the Cu-mediated reaction system, the reactivity decreases in the following order: cross-coupling > intramolecular cyclization > homocoupling.

C−F Bond Cleavage by Intramolecular SN2 Reaction of Alkyl Fluorides with O- and N-Nucleophiles

The nucleophilic substitution of alkyl fluorides was achieved in the intramolecular reactions with O- and N-nucleophiles. The intramolecular defluorinative cyclization reaction was influenced by the nature of nucleophiles, the size of the ring to be formed, and the comformational rigidity of the precursors. Intermolecular nucleophilic substitution reactions of alkyl fluorides under similar reaction conditions were found to be difficult. The stereochemistry study of the current C-F bond cleavage reaction showed a complete configurational inversion, which supports an intramolecular S(N)2 reaction mechanism.

Stereoselective monofluoromethylation of N-tert-butylsulfinyl ketimines using pregenerated fluoro(phenylsulfonyl)methyl anion.

Pregeneration of fluoro(phenylsulfonyl)methyl anion (PhSO(2)CHF(-)) paves the way for the efficient and highly stereoselective monofluoromethylation of (R)-N-tert-butylsulfinyl ketimines. The stereocontrol mode of the present diastereoselective monofluoromethylation of ketimines is different from the previously known nucleophilic fluoroalkylation of (R)-N-tert-butylsulfinyl aldimines, which suggests that a cyclic six-membered transition state (rather than a nonchelation controlled one) is involved in the current ketimine reaction.

Synthesis of Fluorinated β-Ketosulfones and gem-Disulfones by Nucleophilic Fluoroalkylation of Esters and Sulfinates with Di- and Monofluoromethyl Sulfones

An efficient and practically useful method for the preparation of alpha-functionalized mono- and difluoro(phenylsulfonyl)methanes by using a nucleophilic fluoroalkylation methodology was developed. Alpha,alpha-difluoro-beta-ketosulfones, alpha-monofluoro-beta-ketosulfones, and alpha-fluoro disulfones were successfully prepared in excellent yields by nucleophilic fluoroalkylation of esters and sulfinates with PhSO(2)CF(2)H and PhSO(2)CH(2)F reagents.

Nucleophilic Fluoromethylation of Aldehydes with Fluorobis(phenylsulfonyl)methane: The Importance of Strong Li–O Coordination and Fluorine Substitution for CC Bond Formation†

Recently, the selective introduction of fluorinated moieties into organic molecules with a-fluorinated carbanions has attracted substantial interest in organic synthesis, owing to the increasingly important applications of selectively fluorinated organics in life and materials sciences. In particular, a-fluoro(phenylsulfonyl)methane (FSM) derivatives, such as difluoromethyl phenyl sulfone (PhSO2CF2H), fluoromethyl phenyl sulfone (PhSO2CH2F), and fluorobis(phenylsulfonyl)methane (FBSM), have been extensively studied as excellent precursors of a-fluorinated carbanions for nucleophilic diand monofluoromethylations. In this context, FBSM, a reagent independently reported by Shibata et al. and our group in 2006, 4] has been widely recognized as a robust nucleophilic monofluoromethylating agent for many applications, including catalytic enantioselective monofluoromethylation reactions. However, although FBSM reacts with a great variety of electrophiles, its nucleophilic addition reaction with aldehydes still remains a challenge. Very recently, Shibata et al. reported that “FBSM failed to undergo nucleophilic addition to aldehydes regardless of the reaction conditions, leading instead to starting materials by a retro-type reaction”, and they also reasoned that “this behavior presumably results from the instability of the resulting b-hydroxy-a-fluorobis(phenylsulfonyl)methanes caused by the steric hindrance of the two phenylsulfonyl groups” (Scheme 1). Prompted by their report, herein we wish to disclose our remarkable success in the efficient nucleophilic addition of FBSM to aldehydes. Our study shows that both the strong Li–O coordination at low temperatures and fluorine substitution play very important roles in the successful nucleophilic addition of FBSM to aldehydes, which provides new intriguing insights into the nucleophilic fluoroalkylation reactions with a-fluorinated carbanions. The nucleophilic addition reaction of FBSM to aldehydes was tested by using benzaldehyde (1a) as a model substrate (Table 1). When lithium hexamethyldisilazide (LiHMDS)

Chlorodifluoromethyl phenyl sulfone: a novel non-ozone-depleting substance-based difluorocarbene reagent for O- and N-difluoromethylations

Chlorodifluoromethyl phenyl sulfone, a previously unknown compound that can be readily prepared from non-ODS-based precursors, was found to act as a robust difluorocarbene reagent for O- and N-difluoromethylations.