Solvents represent one of the major contributions to the environmental impact of fine‐chemical synthesis. As a result, the use of environmentally friendly solvents in widely employed reactions is a challenge of vast real interest in contemporary organic chemistry. Within this Review, a great variety of examples showing how cyclopentyl methyl ether has been established as particularly useful for this purpose are reported. Indeed, its low toxicity, high boiling point, low melting point, hydrophobicity, chemical stability towards a wide range of conditions, exceptional stability towards the abstraction of hydrogen atoms, relatively low latent heat of vaporization, and the ease with which it can be recovered and recycled enable its successful employment as a solvent in a wide range of synthetic applications, including organometallic chemistry, catalysis, biphasic reactions, oxidations, and radical reactions.
Since the introduction of 2-methyltetrahydrofuran as an useful alternative to the classical tetrahydrofuran, there has been a continuous interest in the synthetic community operating at academic and industrial towards it. In particular, the much higher stability that basic organometallic reagents display in 2-methyltetrahydrofuran makes it suitable for processes involving such sensitive species including asymmetric transformations. The easy formation of an azeotropic mixture with water, the substantial immiscibility with water, and the fact it derives from natural sources (corncobs or bagasse), allow to consider it in agreement with the Anastas’ Geen Chemistry principles. In this minireview, selected examples of its employment in organometallic transformations ranging from carbanions to radical and transition metal-catalyzed processes are provided.Graphical abstract
The first direct and straightforward nucleophilic fluoromethylation of organic compounds is reported. The tactic employs a "fleeting" lithium fluorocarbenoid (LiCHF) generated from commercially available fluoroiodomethane. Precise reaction conditions were developed for the generation and synthetic exploitation of such a labile species. The versatility of the strategy is showcased in ca. 50 examples involving a plethora of electrophiles. Highly valuable chemicals such as fluoroalcohols, fluoroamines, and fluoromethylated oxygenated heterocycles could be prepared in very good yields through a single synthetic operation. The scalability of the reaction and its application to complex molecular architectures (e.g., steroids) are documented.
An
expeditious, high-yielding synthesis of rare α-fluoroepoxides
and α-fluoroaziridines through the addition of the unkown fluoroiodomethyllithium
(LiCHIF)formed via deprotonation the commercially available
fluoroiodomethane with
a lithium amide baseto carbonyl-like compounds is documented.
The ring-closure reactions,
leading to α-fluorinated three-membered heterocycles, rely on
the diversely reactive C–I and C–F bonds. Excellent
chemoselectivity was observed in the presence of
highly sensitive functionalitiesaldehyde, ketone, nitrile,
alkenewhich
remained untouched during the homologation sequence.
The addition of carbon (Grignard and organolithium reagents) and hydride nucleophiles (Schwartz reagent) to isocyanates and isothiocyanates constitutes a versatile, direct and high yielding approach to the synthesis of functionalized (thio)amide derivatives including haloamides and formamides. The chemoselective delivery of a nucleophilic (eventually configurationally stable) organometallic species to a given iso(thio)cyanate is the crucial parameter for the success of the strategy. Thus, the influence of the factors governing classical methodologies (e.g. dehydrative condensation) such as steric hindrance and electronic properties of the reactants become practically negligible.
The acylation of α-substituted carbanion-type reagents (MCR1R2X; X = halogen, OR, SR, NR3R4, SeR, etc.) with Weinreb amides constitutes a highly versatile and flexible approach for accessing α-functionalized ketones. In this short review we will present a series of transformations—from our own and the work of others—documenting the general applicability of the methodology. Chemoselectivity is uniformly manifested including for critical substrates featuring additional electrophilic functionalities or sterically demanding elements. Importantly, the stereochemical information contained in the Weinreb amides can be fully transferred to the targeted ketones without affecting the optical purity. The protocol is also applicable to chiral carbanions generated through sparteine-mediated asymmetric deprotonation: the careful design of the experimental procedure allows recycling of the sparteine and the Weinreb ‘amine’ (N,O-dimethylhydroxylamine), thus improving the sustainability perspective of the processes.1 Introduction1.1 The Problem of the Synthesis of α-Substituted Ketones1.2 Weinreb Amides: General Features and Preparation2 Synthesis of α-Substituted Ketones2.1 α-Haloketones2.2 Synthesis of α-Cyanoketones2.3 Synthesis of α-Oxyketones2.4 Synthesis of β-Oxo Thioethers (α-Thioketones)2.5 Synthesis of Chiral α-Oxy and α-Nitrogen Ketones via the Sparteine-Mediated Generation of Optically Active Organolithiums2.6 Synthesis of α-Selenomethyl Ketones2.7 Reactivity of α-Phosphorus Carbanions with Weinreb Amides2.8 Modification of the Weinreb Amide Core: The CLAmP Reagent3 Competing Attack of Nucleophiles at More Reactive Electrophilic Sites than Weinreb Amides4 Conclusions
The transfer of a reactive nucleophilic CH2X unit into a preformed bond enables the introduction of a fragment featuring the exact and desired degree of functionalization through a single synthetic operation. The instability of metallated α-organometallic species often poses serious questions regarding the practicability of using this conceptually intuitive and simple approach for forming C-C or C-heteroatom bonds. A deep understanding of processes regulating the formation of these nucleophiles is a precious source of inspiration not only for successfully applying theoretically feasible transformations (i.e. determining how to employ a given reagent), but also for designing new reactions which ultimately lead to the introduction of molecular complexity via short experimental sequences.
The nucleophilic addition of widely available and variously functionalized organolithium reagents to isothiocyanates represents a straightforward, high-yielding, one-pot method to access secondary thioamides. The simple reaction conditions required and the broad scope (>50 cases examples) makes it a robust and reliable method to access both simple and complex thioamides, including enantiopure ones. Noxious and unpleasant-smelling sulfurating agents, usually employed in the literature established methods, are avoided during the whole synthetic procedure thus, rendering the protocol highly attractive, also for sustainability aspects.
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