羰基兼容的氟代反应及远端氟代脂肪酮合成的近期进展

含氟化合物在医药、农药以及材料领域有着广泛的应用, 然而温和而高效的构建sp³碳氟键却极具挑战性. 氟代脂肪酮类化合物是一类重要的含氟合成砌块. 本文将从碳氢键氟化、脱羧脱硼氟化、双键氟化、开环氟化四个方面简要概述近年来羰基兼容的氟代反应以及在合成远端氟代脂肪酮方面取得的重要进展.     

微波作用下卤素交换氟化制备氟代苯甲醛及二苯甲酮类化合物

在微波作用下,采用高效催化剂体系,于中等极性非质子溶剂中经卤素交换氟化高效制备了系列含氟芳香醛(酮)类化合物,产品收率53·3%~92·6%,反应时间较常规加热最多可缩短80%以上。采用中等极性反应溶剂,还可突出表现出微波对反应促进的“非热效应”,从而大大拓宽了氟化反应溶剂的选择范围。     

One‐Pot Synthesis of Pyrazoles through a Four‐Step Cascade Sequence

A one‐pot synthesis of 3,4,5‐ and 1,3,5‐pyrazoles from tertiary propargylic alcohols and para‐tolylsulfonohydrazide has been accomplished. The pyrazoles are formed through a four‐step cascade sequence, including FeCl₃‐catalyzed propargylic substitution, aza‐Meyer–Schuster rearrangement, base‐mediated 6π electrocyclization, and thermal [1,5] sigmatropic shift. In this reaction, the 3,4,5‐ and 1,3,5‐pyrazoles are produced selectively according to different substituents in the starting alcohols.     

One‐Pot,Three‐Component Sulfonimidamide Synthesis Exploiting the Sulfinylamine Reagent N‐Sulfinyltritylamine,TrNSO

Sulfonimidamides are increasingly important molecules in medicinal chemistry and agrochemistry, but their preparation requires lengthy synthetic sequences, which has likely limited their use. We describe a one‐pot de novo synthesis of sulfonimidamides from widely available organometallic reagents and amines. This convenient and efficient process uses a stable sulfinylamine reagent, N‐sulfinyltritylamine (TrNSO), available in one step on 10 gram scale, as a linchpin. In contrast to classical approaches starting from thiols or their derivatives, our TrNSO‐based approach facilitates the rapid assembly of the three reaction components into a variety of differentially substituted sulfonimidamides containing medicinally relevant moieties, including pyridines and indoles. Analogues of the sulfonamide‐containing COX‐2 inhibitor Celecoxib were prepared and evaluated.     

Multicomponent One‐pot Reactions Towards the Synthesis of Stereoisomers of Dipicolylamine Complexes

Reported are multi‐component one‐pot syntheses of chiral complexes [M(L^ROR′)Cl₂] or [M(L^RSR′)Cl₂] from the mixture of an N‐substituted ethylenediamine, pyridine‐2‐carboxaldehyde, a primary alcohol or thiol and MCl₂ utilizing in‐situ formed cyclized Schiff bases where a C?O bond, two stereocenters, and three C?N bonds are formed (M=Zn, Cu, Ni, Cd; R=Et, Ph; R′=Me, Et, nPr, nBu). Tridentate ligands L^ROR′ and L^RSR′ comprise two chiral centers and a hemiaminal ether or hemiaminal thioether moiety on the dipicolylamine skeleton. Syn‐[Zn(L^PhOMe)Cl₂] precipitates out readily from the reaction mixture as a major product whereas anti‐[Zn(L^PhOMe)Cl₂] stays in solution as minor product. Both syn‐[Zn(L^PhOMe)Cl₂] and anti‐[Zn(L^PhOMe)Cl₂] were characterized using NMR spectroscopy and mass spectrometry. Solid‐state structures revealed that syn‐[Zn(L^PhOMe)Cl₂] adopted a square pyramidal geometry while anti‐[Zn(L^PhOMe)Cl₂] possesses a trigonal bipyramidal geometry around the Zn centers. The scope of this method was shown to be wide by varying the components of the dynamic coordination assembly, and the structures of the complexes isolated were confirmed by NMR spectroscopy, mass spectrometry, and X‐ray crystallography. Syn complexes were isolated as major products with Zn^II and Cu^II, and anti complexes were found to be major products with Ni^II and Cd^II. Hemiaminals and hemiaminal ethers are known to be unstable and are seldom observed as part of cyclic organic compounds or as coordinated ligands assembled around metals. It is now shown, with the support of experimental results, that linear hemiaminal ethers or thioethers can be assembled without the assistance of Lewis acidic metals in the multi‐component assembly, and a possible pathway of the formation of hemiaminal ethers has been proposed.     

Reactions of the Carbonyl Group in Fluorinated Ketones

The chemistry of polyfluorinated ketones has recently received a great deal of attention.

1 A. Ya. Yakoubovich, Usp. Chim. 25, 3 (1956).

2 H. P. Braendlin and E. T. McBee in: Advances in Fluorine Chemistry. Butterworths, London 1963, Vol. 3, p. 1.

3 The review by Braendlin and McBee [2] does not deal only with perfluorinated ketones; moreover, though published in 1963, it is already outdated. The papers discussed in [1,2] will not be reviewed in the present article.

. The carbonyl and imino groups of the fluorinated ketones and their imines react in many different ways. In particular, the electron-attracting perfluoroalkyl groups intensify the electrophilic properties and weaken the nucleophilic properties of the carbonyl group. The perfluoroalkyl group also hinders the heterolytic removal of the hydroxyl group from adducts by reducing the stability of the carbonium ion . The increased electrophilicity of the carbonyl group and the increased stability of the addition products leads not only to a change in reactivity in the characteristic ketone reactions, but also to numerous new reactions which are not observed with non-fluorinated ketones. Thus it is possible to synthesize a wide variety of fluoroorganic compounds from perfluorinated ketones.

4 We have been concerned mainly with hexafluoroacetone, since in addition to being the most readily available and simplest perfluorinated ketone, this is also a typical representative of this class of compounds.

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AgF‐Mediated Fluorinative Cross‐Coupling of Two Olefins: Facile Access to α‐CF3 Alkenes and β‐CF3 Ketones

A AgF‐mediated fluorination with a concomitant cross‐coupling between a gem‐difluoroolefin and a non‐fluorinated olefin is reported. This highly efficient method provides facile access to both α‐CF₃ alkenes and β‐CF₃ ketones, which otherwise remain challenging to be directly prepared. The application of this method is further demonstrated by the synthesis of bioactive isoxazoline derivatives. This approach represents a conceptually novel route to trifluoromethylated compounds that combines the in situ generation of the CF₃ moiety and a C? H functionalization in a single reaction system.     

Synthesis and Duplex‐Stabilizing Properties of Fluorinated N‐Methanocarbathymidine Analogues Locked in the C3′‐endo Conformation

The efficient synthesis, antiviral activity, and duplex‐stabilizing properties of both isomers of the 2′‐fluoro analogue of Northern methanocarbathymidine (N‐MCT), 2 and 3 , are reported. We show that 2′‐F incorporation on the N‐MCT scaffold has a strong stabilizing effect on duplex thermal stability.     

Chemo‐ and Stereoselective Iron‐Catalyzed Hydrosilylation of Ketones

The reduction of ketones with polymethylhydrosiloxane (PMHS) gives the corresponding alcohols in good to excellent yield applying iron‐based catalyst systems. In the case of prochiral ketones, the use of Fe(OAc)₂/(S,S)‐Me‐DuPhos leads to high enantioselectivity up to 99 % ee. The reaction proceeds in the presence of several functional groups such as esters, halides as well as conjugated double bonds, with high chemoselectivity. The advantage of this protocol is that the reaction requires no activating agents or additives.     

One‐Step Hydrothermal Synthesis of Carboxyl‐Functionalized Upconversion Phosphors for Bioapplications

In this paper, we report a facile one‐step hydrothermal method to synthesize phase‐, size‐, and shape‐controlled carboxyl‐functionalized rare‐earth fluorescence upconversion phosphors by using a small‐molecule binary acid, such as malonic acid, oxalic acid, succinic acid, or tartaric acid as capping agent. The crystals, from nano‐ to microstructures with diverse shapes that include nanospheres, microrods, hexagonal prisms, microtubes, microdisks, polygonal columns, and hexagonal tablets, can be obtained with different reaction times, reaction temperatures, molar ratios of capping agent to sodium hydroxide, and by varying the binary acids. Fourier transform infrared, thermogravimetric analysis, and upconversion luminescence spectra measurements indicate that the synthesized NaYF₄:Yb/Er products with hydrophilic carboxyl‐functionalized surface offer efficient upconversion luminescent performance. Furthermore, the antibody/secondary antibody conjugation can be realized by the carboxyl‐functionalized surfaces of the upconversion phosphors, thus indicating the potential bioapplications of these kinds of materials.     

铃木-宫浦羰化反应在合成二芳基甲酮中的应用

近年来,钯催化的芳基卤化物和芳基硼酸化合物的羰化偶联反应发展十分迅速。到目前为止,大量硼酸化合物、钯催化剂前体、配体和羰基源被用来合成二芳基甲酮,此类化合物在工业中间体、染料、药剂、天然产物等领域有着广泛的应用。本文从钯催化剂体系、转金属促进剂、羰基源及其应用方面综述了铃木-宫蒲（Suzuki-Miyaura or Suzuki）羰化反应的研究进展。钯催化剂体系从均相和非均相体系两方面介绍,其中均相催化体系包括钯催化剂前驱体、磷配体、氮杂卡宾配体的研究进展;非均相催化体系主要介绍了活性炭、石墨烯、官能化硅胶、四氧化三铁等载体多种固载钯催化剂的应用。特戊酸添加剂可改善转金属化过程,有效加速羰化偶联反应。经典的羰化Suzuki反应一般需要气体钢瓶提供压力较高的一氧化碳气体。尽管近期一些研究实现了常压一氧化碳气球作为羰基供给源,使用一氧化碳释放分子（CO-releasing molecule,CORM）替代剧毒危险的一氧化碳气体可实现更为安全绿色的羰化反应进程。在双管反应器中,有机CORM可控降解释放一氧化碳,为钯催化羰基偶联反应提供CO。在微波辐射下,过渡金属羰基化合物可为羰基化反应原位直接提供CO。     

Copper‐Catalyzed Cyanomethylation of Allylic Alcohols with Concomitant 1,2‐Aryl Migration: Efficient Synthesis of Functionalized Ketones Containing an α‐Quaternary Center

A copper‐catalyzed alkylation of allylic alcohols by alkyl nitriles with concomitant 1,2‐aryl migration was developed. Formation of the alkyl nitrile radical was followed by its intermolecular addition to alkenes and the migration of a vicinal aryl group with the concomitant generation of a carbonyl functionality to complete the domino sequence. Mechanistic studies suggested that 1,2‐aryl migration proceeded through a radical pathway (neophyl rearrangement). The protocol provided an efficient route to functionalized ketones containing an α‐quaternary center.     

Unified,Efficient, and Scalable Synthesis of Halichondrins: Zirconium/Nickel‐Mediated One‐Pot Ketone Synthesis as the Final Coupling Reaction

Unified, efficient, and scalable syntheses of the halichondrin natural products are reported. A newly developed Zr/Ni‐mediated one‐pot ketone synthesis was used to couple the two halves of the final product at a late stage in the synthesis. With the use of a slight excess of the left halves, the desired ketones were isolated in yields of 80–90 %. The halichondrins were obtained from these ketones in two steps, namely desilylation and [5,5]‐spiroketal formation. The new synthetic route was effective for the total synthesis of all members in the homohalichondrin subgroup. The scalability of this process was demonstrated with halichondrin B; 150 mg of halichondrin B (68 % overall yield) were obtained from 200 mg of the right‐half precursor.     

One‐pot Synthesis of Nitrogen and Phosphorus Co‐doped Graphene and Its Use as High‐performance Electrocatalyst for Oxygen Reduction Reaction

In this study, N,P co‐doped graphene (NPG) was prepared by a one‐step pyrolysis using a mixture of graphene oxide and hexachlorocyclotriphosphazene (HCCP), in which HCCP was used as both the N and P source. Furthermore, it is shown that NPG electrodes, as efficient metal‐free electrocatalysts, have a high onset potential, high current density, and long‐term stability for the oxygen reduction reaction.     

Ketones to amides via a formal Beckmann rearrangement in ‘one pot’: a solvent-free reaction promoted by anhydrous oxalic acid. Possible analogy with the Schmidt reaction

A variety of ketones can be directly converted into the secondary amides expected from a Beckmann rearrangement of the corresponding oximes in high yield, by heating them with hydroxylamine hydrochloride and anhydrous oxalic acid at ∼100°C for 4-12 h. (Aromatic aldehydes afforded mixtures of nitrile and amide.) The transformation is apparently (kinetically) driven by the coupled decomposition of oxalic acid (to CO+CO₂) via the fragmentation of an intermediate oxime mono-oxalate. However, an alternative pathway, mechanistically analogous to the Schmidt reaction, is not only equally likely but may well be general for the Beckmann rearrangement.